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26 pages, 15410 KiB

Open AccessArticle

Repurposing Quinacrine for Treatment of Malignant Mesothelioma: In-Vitro Therapeutic and Mechanistic Evaluation

by Nishant S. Kulkarni, Bhuvaneshwar Vaidya, Vineela Parvathaneni, Debarati Bhanja and Vivek Gupta

Int. J. Mol. Sci. 2020, 21(17), 6306; https://doi.org/10.3390/ijms21176306 - 31 Aug 2020

Cited by 14 | Viewed by 6136

Abstract

Malignant mesothelioma (MM) is a rare type of cancer primarily affecting mesothelial cells lining the pleural cavity. In this study, we propose to repurpose quinacrine (QA), a widely approved anti-malarial drug, for Malignant Pleural Mesothelioma (MPM) treatment. QA demonstrates high degree of cytotoxicity [...] Read more.

Malignant mesothelioma (MM) is a rare type of cancer primarily affecting mesothelial cells lining the pleural cavity. In this study, we propose to repurpose quinacrine (QA), a widely approved anti-malarial drug, for Malignant Pleural Mesothelioma (MPM) treatment. QA demonstrates high degree of cytotoxicity against both immortalized and primary patient-derived cell lines with sub-micromolar 50% inhibitory concentration (IC₅₀) values ranging from 1.2 µM (H2452) to 5.03 µM (H28). Further, QA also inhibited cellular migration and colony formation in MPM cells, demonstrated using scratch and clonogenic assays, respectively. A 3D-spheroid cell culture experiment was performed to mimic in-vivo tumor conditions, and QA was reported to be highly effective in this simulated cellular model. Anti-angiogenic properties were also discovered for QA. Autophagy inhibition assay was performed, and results revealed that QA successfully inhibited autophagy process in MPM cells, which has been cited to be one of the survival pathways for MPM. Annexin V real-time apoptosis study revealed significant apoptotic induction in MPM cells following QA treatment. Western blots confirmed inhibition of autophagy and induction of apoptosis. These studies highlight anti-mesothelioma efficacy of QA at low doses, which can be instrumental in developing it as a stand-alone treatment strategy for MPM. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 4422 KiB

Open AccessArticle

Resveratrol Suppresses the Growth and Enhances Retinoic Acid Sensitivity of Anaplastic Thyroid Cancer Cells

by Yi-Tian Li, Xiao-Ting Tian, Mo-Li Wu, Xu Zheng, Qing-You Kong, Xiao-Xin Cheng, Guang-Wen Zhu, Jia Liu and Hong Li

Int. J. Mol. Sci. 2018, 19(4), 1030; https://doi.org/10.3390/ijms19041030 - 29 Mar 2018

Cited by 38 | Viewed by 5731

Abstract

Anaplastic thyroid cancer (ATC) is a highly lethal undifferentiated malignancy without reliable therapies. Retinoic acid (RA) has been employed to promote redifferentiation of thyroid cancers by increasing their I¹³¹ uptake and radio-sensitivity, but its effect(s) on ATCs has not yet been ascertained. [...] Read more.

Anaplastic thyroid cancer (ATC) is a highly lethal undifferentiated malignancy without reliable therapies. Retinoic acid (RA) has been employed to promote redifferentiation of thyroid cancers by increasing their I¹³¹ uptake and radio-sensitivity, but its effect(s) on ATCs has not yet been ascertained. Likewise, resveratrol induces cancer redifferentiation but, also in this case, its effects on ATCs remain unknown. These issues have been addresses in the current study using three human ATC cell lines (THJ-11T, THJ-16T, and THJ-21T) through multiple experimental approaches. The results reveal that RA exerts a small inhibitory effect on these cell lines. In comparison with normally cultured cells, the total cell number in resveratrol-treated THJ-16T and THJ-21T cultures significantly decreased (p < 0.05), and this effect was accompanied by reduced Cyclin D1 immuno-labeling, increased apoptotic fractions, and distinct caspase-3 activation. Resveratrol failed to inhibit growth but enhanced RA sensitivity of THJ-11T cells, suppressed peroxisome proliferator-activated receptor-β/δ (PPAR-β/δ), and upregulated cellular retinoic acid-binding protein 2 (CRABP2) and retinoic acid receptor beta (RAR-β) expression. Increased thyroglobulin (Tg) and E-cadherin levels and appearance of membranous E-cadherin were evidenced in resveratrol-treated THJ-11T cells. Our results demonstrate for the first time: (1) the therapeutic value of resveratrol by itself or in combination with RA in the management of ATCs, (2) the capacity of resveratrol to overcome RA resistance in ATC cells by reprogramming CRABP2/RAR- and fatty acid-binding protein 5 (FABP5)/PPAR-β/δ-mediated RA signaling, and (3) the redifferentiating potential of resveratrol in ATC cells. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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12 pages, 1385 KiB

Open AccessArticle

The rs2910164 Genetic Variant of miR-146a-3p Is Associated with Increased Overall Mortality in Patients with Follicular Variant Papillary Thyroid Carcinoma

by Marta Kotlarek, Anna Kubiak, Małgorzata Czetwertyńska, Michał Świerniak, Wojciech Gierlikowski, Monika Kolanowska, Elwira Bakuła-Zalewska, Sissy M. Jhiang, Krystian Jażdżewski and Anna Wójcicka

Int. J. Mol. Sci. 2018, 19(3), 655; https://doi.org/10.3390/ijms19030655 - 26 Feb 2018

Cited by 13 | Viewed by 5608

Abstract

Aberrant expression of the sodium-iodide symporter (NIS) and the resistance to post-operative radioactive iodide treatment is a crucial cause of higher mortality of some thyroid cancer patients. In this study, we analyzed the impact of miR-146a on the expression and function of NIS [...] Read more.

Aberrant expression of the sodium-iodide symporter (NIS) and the resistance to post-operative radioactive iodide treatment is a crucial cause of higher mortality of some thyroid cancer patients. In this study, we analyzed the impact of miR-146a on the expression and function of NIS and on the overall survival of thyroid cancer patients. The study included 2441 patients (2163 women; 278 men); including 359 cases with follicular variant of papillary thyroid carcinoma (fvPTC). miR:NIS interactions were analyzed in cell lines using in vivo binding and inhibition assays and radioactive iodine uptake assays. Tumor/blood DNA was used for rs2910164 genotyping. Overall survival was assessed retrospectively. In the results, we showed that miR-146a-3p directly binds to and inhibits NIS. Inhibition of miR-146a-3p restores the expression and function of NIS, increasing radioactive iodine uptake. Rs2910164 functional variant within miR-146a-3p is associated with increased overall mortality among fvPTC female patients. The deaths per 1000 person-years were 29.7 in CC carriers vs. 5.08 in GG/GC-carriers (HR = 6.21, p = 0.006). Higher mortality of CC vs. GG/GC carriers was also observed in patients with lower clinical stage (HR = 22.72, p < 0.001), smaller tumor size (pT1/pT2) (HR = 25.05, p < 0.001), lack of extrathyroidal invasion (HR = 9.03, p = 0.02), lack of nodular invasion (HR = 7.84, p = 0.002), lack of metastases (HR = 6.5, p = 0.005) and older (age at diagnosis >50 years) (HR = 7.8, p = 0.002). MiR-146a-3p underwent somatic mutations in 16.1% of analyzed specimens, mainly towards the deleterious C allele. In this report we propose a novel molecular marker of the clinical outcome of fvPTC patients. Rs2910164 increases the overall mortality with inhibition of NIS and disruption of radioiodine uptake as a possible mechanism. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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10 pages, 2951 KiB

Open AccessCommunication

Identification of a Rare Germline Heterozygous Deletion Involving the Polycistronic miR-17–92 Cluster in Two First-Degree Relatives from a BRCA 1/2 Negative Chilean Family with Familial Breast Cancer: Possible Functional Implications

by Tomás De Mayo, Annemarie Ziegler, Sebastián Morales and Lilian Jara

Int. J. Mol. Sci. 2018, 19(1), 321; https://doi.org/10.3390/ijms19010321 - 22 Jan 2018

Cited by 4 | Viewed by 5819

Abstract

Micro-RNAs (miRNAs) have emerged as novel gene expression regulators. Recent evidence strongly suggests a role for miRNAs in a large variety of cancer-related pathways. Different studies have shown that 18.7 to 37% of all human miRNA genes are clustered. miR-17–92 polycistronic cluster overexpression [...] Read more.

Micro-RNAs (miRNAs) have emerged as novel gene expression regulators. Recent evidence strongly suggests a role for miRNAs in a large variety of cancer-related pathways. Different studies have shown that 18.7 to 37% of all human miRNA genes are clustered. miR-17–92 polycistronic cluster overexpression is associated with human hematolymphoid and solid malignancies including breast cancer (BC). Here, we report the identification of rs770419845, a rare 6 bp deletion located within the polycistronic miR-17–92 cluster, in two first-degree relatives from a Chilean family with familial BC and negative for point mutations in BRCA 1/2 genes. The deletion was identified by Sanger sequencing when 99 BRCA1/2 mutation-negative BC cases with a strong family history were initially screened. In silico analysis predicts that rs770419845 affects the secondary structure and stability of the pre-miR-17–pre-miR-18 region and the entire 17–92 cluster. The deletion was screened in 458 high-risk BRCA1/2-negative Chilean families and 480 controls. rs770419845 was not detected in any control but identified in a single family with two cases of BC and other cancers. Both BC cases, the mother and her daughter, carried the deletion. Based on bioinformatic analyses, the location of the deletion and its low frequency, we presume rs770419845 may be a pathogenic variant. Functional studies are needed to support this hypothesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 16758 KiB

Open AccessArticle

B-Myb Is Up-Regulated and Promotes Cell Growth and Motility in Non-Small Cell Lung Cancer

by Yuelei Jin, Huifang Zhu, Wei Cai, Xiaoyan Fan, Yitao Wang, Yulong Niu, Fangzhou Song and Youquan Bu

Int. J. Mol. Sci. 2017, 18(6), 860; https://doi.org/10.3390/ijms18060860 - 27 May 2017

Cited by 42 | Viewed by 6760

Abstract

B-Myb is a transcription factor that is overexpressed and plays an oncogenic role in several types of human cancers. However, its potential implication in lung cancer remains elusive. In the present study, we have for the first time investigated the expression profile of [...] Read more.

B-Myb is a transcription factor that is overexpressed and plays an oncogenic role in several types of human cancers. However, its potential implication in lung cancer remains elusive. In the present study, we have for the first time investigated the expression profile of B-Myb and its functional impact in lung cancer. Expression analysis by quantificational real-time polymerase chain reaction (qRT-PCR) and immunohistochemistry demonstrated that B-Myb expression is aberrantly overexpressed in non-small cell lung cancer (NSCLC), and positively correlated with pathologic grade and clinical stage of NSCLC. A gain-of-function study revealed that overexpression of B-Myb significantly increases lung cancer cell growth, colony formation, migration, and invasion. Conversely, a loss-of-function study showed that knockdown of B-Myb decreases cell growth, migration, and invasion. B-Myb overexpression also promoted tumor growth in vivo in a NSCLC xenograft nude mouse model. A molecular mechanistic study by RNA-sequencing (RNA-seq) analysis showed that B-Myb overexpression causes up-regulation of various downstream genes (e.g., COL11A1, COL6A1, FN1, MMP2, NID1, FLT4, INSR, and CCNA1) and activation of multiple critical pathways (e.g., extracellular signal-regulated kinases (ERK) and phosphorylated-protein kinase B (Akt) signaling pathways) involved in cell proliferation, tumorigenesis, and metastasis. Collectively, our results indicate a tumor-promoting role for B-Myb in NSCLC and thus imply its potential as a target for the diagnosis and/or treatment of NSCLC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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14 pages, 8769 KiB

Open AccessArticle

Overexpression of Transforming Acidic Coiled Coil‑Containing Protein 3 Reflects Malignant Characteristics and Poor Prognosis of Glioma

by Ying Sun, Yu Tian, Guang-Zhi Wang, Shi-Hong Zhao, Bo Han, Yong-Li Li and Chuan-Lu Jiang

Int. J. Mol. Sci. 2017, 18(3), 235; https://doi.org/10.3390/ijms18030235 - 4 Mar 2017

Cited by 8 | Viewed by 5621

Abstract

Gliomas are malignant primary brain tumors with poor prognosis. Recently, research was indicative of a tight connection between tumor malignancy and genetic alterations. Here, we propose an oncogenic implication of transforming acidic coiled-coil-containing protein 3 (TACC3) in gliomas. By comprehensively analyzing the Chinese [...] Read more.

Gliomas are malignant primary brain tumors with poor prognosis. Recently, research was indicative of a tight connection between tumor malignancy and genetic alterations. Here, we propose an oncogenic implication of transforming acidic coiled-coil-containing protein 3 (TACC3) in gliomas. By comprehensively analyzing the Chinese glioma genome atlas (CGGA) and publicly available data, we demonstrated that TACC3 were overexpressed along with glioma grade and served as an independent negative prognostic biomarker for glioma patients. Functions’ annotations and gene sets’ enrichment analysis suggested that TACC3 may participate in cell cycle, DNA repair, epithelium-mesenchymal transition and other tumor-related biological processes and molecular pathways. Patients with high TACC3 expression showed CD133⁺ stem cell properties, glioma plasticity and shorter overall survival time under chemo-/radio-therapy. Additionally, a TACC3 associated the miRNA-mRNA network was constructed based on in silico prediction and expression pattern, which provide a foundation for further detection of TACC3-miRNA-mRNA axis function. Collectively, our observations identify TACC3 as an oncogene of tumor malignancy, as well as a prognostic and motoring biomarker for glioma patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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13 pages, 2614 KiB

Open AccessArticle

Sphingosine Kinase-1 Involves the Inhibitory Action of HIF-1α by Chlorogenic Acid in Hypoxic DU145 Cells

by Myoung-Sun Lee, Seon-Ok Lee, Kyu-Ri Kim and Hyo-Jeong Lee

Int. J. Mol. Sci. 2017, 18(2), 325; https://doi.org/10.3390/ijms18020325 - 4 Feb 2017

Cited by 25 | Viewed by 9211

Abstract

Hypoxia enhances cancer development in a solid tumor. Hypoxia-inducible factor-1 α (HIF-1α) is a transcription factor that is dominantly expressed under hypoxia in solid tumor cells and is a key factor that regulates tumor. HIF-1α regulates several target genes involved in many aspects [...] Read more.

Hypoxia enhances cancer development in a solid tumor. Hypoxia-inducible factor-1 α (HIF-1α) is a transcription factor that is dominantly expressed under hypoxia in solid tumor cells and is a key factor that regulates tumor. HIF-1α regulates several target genes involved in many aspects of cancer progression, including angiogenesis, metastasis, anti-apoptosis and cell proliferation as well as imparts resistance to cancer treatment. In this study, we assessed Crataegus Pinnatifida Bunge var. typical Schneider ethanol extract (CPE) for its anti-cancer effects in hypoxia-induced DU145 human prostate cancer cell line. CPE decreased the abundance of HIF-1α and sphingosine kinase-1 (SPHK-1) in hypoxia-induced prostate cancer DU145 cells. CPE decreased HIF-1α and SPHK-1 as well as SPHK-1 activity. Chlorogenic acid (CA) is one of four major compounds of CPE. Compared to CPE, CA significantly decreased the expression of HIF-1α and SPHK-1 as well as SPHK-1 activity in hypoxia-induced DU145 cells. Furthermore, CA decreased phosphorylation AKT and GSK-3β, which are associated with HIF-1α stabilization and affected SPHK-1 in a concentration-dependent manner. We confirmed the mechanism of CA-induced inhibition of HIF-1α by SPHK-1 signaling pathway using SPHK-1 siRNA and SPHK inhibitor (SKI). CA decreased the secretion and cellular expression of VEGF, thus inhibiting hypoxia-induced angiogenesis. Treatment of DU145cells with SPHK1 siRNA and CA for 48 h decreased cancer cell growth, and the inhibitory action of SPHK siRNA and CA on cell growth was confirmed by decrease in the abundance of Proliferating cell nuclear antigen (PCNA). Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 6240 KiB

Open AccessArticle

High-Level γ-Glutamyl-Hydrolase (GGH) Expression is Linked to Poor Prognosis in ERG Negative Prostate Cancer

by Nathaniel Melling, Masoud Rashed, Cornelia Schroeder, Claudia Hube-Magg, Martina Kluth, Dagmar Lang, Ronald Simon, Christina Möller-Koop, Stefan Steurer, Guido Sauter, Frank Jacobsen, Franziska Büscheck, Corinna Wittmer, Till Clauditz, Till Krech, Maria Christina Tsourlakis, Sarah Minner, Hartwig Huland, Markus Graefen, Lars Budäus, Imke Thederan, Georg Salomon, Thorsten Schlomm and Waldemar Wilczak Show full author list Hide full author list

Int. J. Mol. Sci. 2017, 18(2), 286; https://doi.org/10.3390/ijms18020286 - 29 Jan 2017

Cited by 28 | Viewed by 7575

Abstract

γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas [...] Read more.

γ-glutamyl-hydrolase (GGH) is a ubiquitously-expressed enzyme that regulates intracellular folate metabolism for cell proliferation, DNA synthesis, and repair. Employing GGH immunohistochemistry on a tissue microarray with 12,427 prostate cancers, we found that GGH expression was negative to low in normal prostate epithelium, whereas 88.3% of our 10,562 interpretable cancers showed GGH expression. GGH staining was considered as low intensity in 49.6% and as high intensity in 38.6% of cancers. High GGH expression was linked to the TMPRSS2:ERG-fusion positive subset of cancers (p < 0.0001), advanced pathological tumor stage, and high Gleason grade (p < 0.0001 each). Further analysis revealed that these associations were merely driven by the subset of ERG-negative cancers, High GGH expression was weakly linked to early biochemical recurrence in ERG negative cancers (p < 0.0001) and independent from established histo-pathological parameters. Moreover, GGH expression was linked to features of genetic instability, including presence of recurrent deletions at 3p, 5q, 6q, and 10q (PTEN, p ≤ 0.01 each), as well as to accelerated cell proliferation as measured by Ki67 immunohistochemistry (p < 0.0001). In conclusion, the results of our study identify GGH as an ERG subtype specific molecular marker with modest prognostic relevance, which may have clinical relevance if analyzed in combination with other molecular markers. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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12 pages, 1669 KiB

Open AccessArticle

High Intra- and Inter-Tumoral Heterogeneity of RAS Mutations in Colorectal Cancer

by Marion Jeantet, David Tougeron, Gaelle Tachon, Ulrich Cortes, Céline Archambaut, Gaelle Fromont and Lucie Karayan-Tapon

Int. J. Mol. Sci. 2016, 17(12), 2015; https://doi.org/10.3390/ijms17122015 - 1 Dec 2016

Cited by 35 | Viewed by 6101

Abstract

Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS [...] Read more.

Approximately 30% of patients with wild type RAS metastatic colorectal cancer are non-responders to anti-epidermal growth factor receptor monoclonal antibodies (anti-EGFR mAbs), possibly due to undetected tumoral subclones harboring RAS mutations. The aim of this study was to analyze the distribution of RAS mutations in different areas of the primary tumor, metastatic lymph nodes and distant metastasis. A retrospective cohort of 18 patients with a colorectal cancer (CRC) was included in the study. Multiregion analysis was performed in 60 spatially separated tumor areas according to the pathological tumor node metastasis (pTNM) staging and KRAS, NRAS and BRAF mutations were tested using pyrosequencing. In primary tumors, intra-tumoral heterogeneity for RAS mutation was found in 33% of cases. Inter-tumoral heterogeneity for RAS mutation between primary tumors and metastatic lymph nodes or distant metastasis was found in 36% of cases. Moreover, 28% of tumors had multiple RAS mutated subclones in the same tumor. A high proportion of CRCs presented intra- and/or inter-tumoral heterogeneity, which has relevant clinical implications for anti-EGFR mAbs prescription. These results suggest the need for multiple RAS testing in different parts of the same tumor and/or more sensitive techniques. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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11 pages, 5680 KiB

Open AccessArticle

Low Expression of CAPON in Glioma Contributes to Cell Proliferation via the Akt Signaling Pathway

by Shangfeng Gao, Jie Wang, Tong Zhang, Guangping Liu, Lei Jin, Daofei Ji, Peng Wang, Qingming Meng, Yufu Zhu and Rutong Yu

Int. J. Mol. Sci. 2016, 17(11), 1859; https://doi.org/10.3390/ijms17111859 - 18 Nov 2016

Cited by 12 | Viewed by 5611

Abstract

CAPON is an adapter protein for nitric oxide synthase 1 (NOS1). CAPON has two isoforms in the human brain: CAPON-L (long form of CAPON) and CAPON-S (short form of CAPON). Recent studies have indicated the involvement of CAPON in tumorigenesis beyond its classical [...] Read more.

CAPON is an adapter protein for nitric oxide synthase 1 (NOS1). CAPON has two isoforms in the human brain: CAPON-L (long form of CAPON) and CAPON-S (short form of CAPON). Recent studies have indicated the involvement of CAPON in tumorigenesis beyond its classical role in NOS1 activity regulation. In this study, we found that the protein levels of CAPON-S, but not than CAPON-L, were significantly decreased in glioma tissues. Therefore, we established lentivirus-mediated stable cell lines with CAPON-S overexpression or down-regulation, and investigated the role of CAPON-S in the proliferation of glioma cells by using CCK8, EdU, and flow cytometry assays. Overexpression of CAPON-S reduced the cell variability and the percentage of EdU-positive cells, and arrested the cells in the G1 phase in glioma cells. Silencing of CAPON by short-hairpin RNA showed the opposite effects. Furthermore, an intracellular signaling array revealed that overexpression of CAPON-S resulted in a remarkable reduction in the phosphorylation of Akt and S6 ribosomal protein in glioma cells, which was further confirmed by Western blot. These findings suggest that CAPON may function as a tumor suppressor in human brain glioma and that the inactivation of the Akt signaling pathway caused by CAPON-S overexpression may provide insight into the underlying mechanism of CAPON in glioma cell proliferation. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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13 pages, 1856 KiB

Open AccessArticle

PPIC, EMP3 and CHI3L1 Are Novel Prognostic Markers for High Grade Glioma

by Yuan-Feng Gao, Tao Zhu, Chen-Xue Mao, Zhi-Xiong Liu, Zhi-Bin Wang, Xiao-Yuan Mao, Ling Li, Ji-Ye Yin, Hong-Hao Zhou and Zhao-Qian Liu

Int. J. Mol. Sci. 2016, 17(11), 1808; https://doi.org/10.3390/ijms17111808 - 28 Oct 2016

Cited by 41 | Viewed by 6889

Abstract

Current treatment methods for patients diagnosed with gliomas have shown limited success. This is partly due to the lack of prognostic genes available to accurately predict disease outcomes. The aim of this study was to investigate novel prognostic genes based on the molecular [...] Read more.

Current treatment methods for patients diagnosed with gliomas have shown limited success. This is partly due to the lack of prognostic genes available to accurately predict disease outcomes. The aim of this study was to investigate novel prognostic genes based on the molecular profile of tumor samples and their correlation with clinical parameters. In the current study, microarray data (GSE4412 and GSE7696) downloaded from Gene Expression Omnibus were used to identify differentially expressed prognostic genes (DEPGs) by significant analysis of microarray (SAM) between long-term survivors (>2 years) and short-term survivors (≤2 years). DEPGs generated from these two datasets were intersected to obtain a list of common DEPGs. The expression of a subset of common DEPGs was then independently validated by real-time reverse transcription quantitative PCR (qPCR). Survival value of the common DEPGs was validated using known survival data from the GSE4412 and TCGA dataset. After intersecting DEPGs generated from the above two datasets, three genes were identified which may potentially be used to determine glioma patient prognosis. Independent validation with glioma patients tissue (n = 70) and normal brain tissue (n = 19) found PPIC, EMP3 and CHI3L1 were up-regulated in glioma tissue. Survival value validation showed that the three genes correlated with patient survival by Kaplan-Meir analysis, including grades, age and therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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10 pages, 1586 KiB

Open AccessArticle

The Expression and Clinical Outcome of pCHK2-Thr68 and pCDC25C-Ser216 in Breast Cancer

by Huayong Jiang, Bin Wang, Fuli Zhang, Yuanyu Qian, Chia-Chen Chuang, Mingzhen Ying, Yajie Wang and Li Zuo

Int. J. Mol. Sci. 2016, 17(11), 1803; https://doi.org/10.3390/ijms17111803 - 28 Oct 2016

Cited by 5 | Viewed by 5457

Abstract

Checkpoint kinase 2 (CHK2) and cell division cycle 25C (CDC25C) are two proteins involved in the DNA damage response pathway, playing essential roles in maintaining genome integrity. As one of the major hallmarks of abnormal cellular division, genomic instability occurs in most cancers. [...] Read more.

Checkpoint kinase 2 (CHK2) and cell division cycle 25C (CDC25C) are two proteins involved in the DNA damage response pathway, playing essential roles in maintaining genome integrity. As one of the major hallmarks of abnormal cellular division, genomic instability occurs in most cancers. In this study, we identified the functional expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer, as well as its association with breast cancer survival. Tissue microarray analysis using immunohistochemistry was constructed to identify the expression of pCHK2-Thr68 and pCDC25C-Ser216 in 292 female breast cancer patients. The relationship among protein expression, clinicopathological factors (e.g., human epidermal growth factor receptor 2 (HER 2), tumor size, tumor-node-metastasis (TNM) classification), and overall survival of the breast cancer tissues were analyzed using Pearson’s χ-square (χ²) test, Fisher’s exact test, multivariate logistic regression and Kaplan–Meier survival analysis. Significantly higher expressions of pCHK2-Thr68 and pCDC25C-Ser216 were observed in the nucleus of the breast cancer cells compared to the paracancerous tissue (pCHK2-Thr68, 20.38% vs. 0%; pCDC25C-Ser216, 82.26% vs. 24.24%). The expression of pCHK2-Thr68 and pCDC25C-Ser216 in breast cancer showed a positive linear correlation (p = 0.026). High expression of pCHK2-Thr68 was associated with decreased patient survival (p = 0.001), but was not an independent prognostic factor. Our results suggest that pCHK2-Thr68 and pCDC25C-Ser216 play important roles in breast cancer and may be potential treatment targets. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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18 pages, 3355 KiB

Open AccessArticle

by Piotr Donizy, Maciej Kaczorowski, Przemyslaw Biecek, Agnieszka Halon, Teresa Szkudlarek and Rafal Matkowski

Int. J. Mol. Sci. 2016, 17(10), 1619; https://doi.org/10.3390/ijms17101619 - 1 Oct 2016

Cited by 31 | Viewed by 5982

Abstract

GOLPH2 and GOLPH3 are Golgi-related proteins associated with aggressiveness and progression of a number of cancers. Their prognostic significance in melanoma has not yet been analyzed. We performed immunohistochemical analysis for GOLPH2 and GOLPH3 in 20 normal skin, 30 benign nevi and 100 [...] Read more.

GOLPH2 and GOLPH3 are Golgi-related proteins associated with aggressiveness and progression of a number of cancers. Their prognostic significance in melanoma has not yet been analyzed. We performed immunohistochemical analysis for GOLPH2 and GOLPH3 in 20 normal skin, 30 benign nevi and 100 primary melanoma tissue samples and evaluated their expression in three compartments: cancer cells, tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). High levels of both proteins in melanoma cells were associated with characteristics of aggressive disease, and shorter disease-free survival (DFS) and cancer-specific overall survival (CSOS). On the contrary, increased numbers of GOLPH2-positive and GOLPH3-positive TAMs were observed in thinner, non-ulcerated tumors, with brisk lymphocytic reaction and absent lymphangioinvasion. Distant metastases were not observed among patients with high numbers of GOLPH2-positive TAMs. Increased expression of either protein in TAMs was related to prolonged CSOS and DFS. Similarly, GOLPH3-expressing CAFs were more frequent in thin melanomas with low mitotic rate, without ulceration and lymphangioinvasion. Moreover, increased GOLPH3-positive CAFs correlated with the absence of regional or distant metastases, and with longer CSOS and DFS. GOLPH2 expression was not observed in CAFs. Our results suggest that GOLPH2 and GOLPH3 play a role in melanoma progression and are potential targets for molecular-based therapies. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 2827 KiB

Open AccessArticle

Decreased Expression of SRSF2 Splicing Factor Inhibits Apoptotic Pathways in Renal Cancer

by Hanna Kędzierska, Piotr Popławski, Grażyna Hoser, Beata Rybicka, Katarzyna Rodzik, Elżbieta Sokół, Joanna Bogusławska, Zbigniew Tański, Anna Fogtman, Marta Koblowska and Agnieszka Piekiełko-Witkowska

Int. J. Mol. Sci. 2016, 17(10), 1598; https://doi.org/10.3390/ijms17101598 - 28 Sep 2016

Cited by 36 | Viewed by 8516 | Correction

Abstract

Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, [...] Read more.

Serine and arginine rich splicing factor 2(SRSF2) belongs to the serine/arginine (SR)-rich family of proteins that regulate alternative splicing. Previous studies suggested that SRSF2 can contribute to carcinogenic processes. Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer, highly aggressive and difficult to treat, mainly due to resistance to apoptosis. In this study we hypothesized that SRSF2 contributes to the regulation of apoptosis in ccRCC. Using tissue samples obtained from ccRCC patients, as well as independent validation on The Cancer Genome Atlas (TCGA) data, we demonstrate for the first time that expression of SRSF2 is decreased in ccRCC tumours when compared to non-tumorous control tissues. Furthermore, by employing a panel of ccRCC-derived cell lines with silenced SRSF2 expression and qPCR arrays we show that SRSF2 contributes not only to splicing patterns but also to expression of multiple apoptotic genes, including new SRSF2 targets: DIABLO, BIRC5/survivin, TRAIL, BIM, MCL1, TNFRSF9, TNFRSF1B, CRADD, BCL2L2, BCL2A1, and TP53. We also identified a new splice variant of CFLAR, an inhibitor of caspase activity. These changes culminate in diminished caspase-9 activity and inhibition of apoptosis. In summary, we show for the first time that decreased expression of SRSF2 in ccRCC contributes to protection of cancer cells viability. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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12 pages, 2604 KiB

Open AccessArticle

Elevated Expression of Calpain-4 Predicts Poor Prognosis in Patients with Gastric Cancer after Gastrectomy

by Peike Peng, Lingqiang Min, Shushu Song, Junjie Zhao, Lili Li, Caiting Yang, Miaomiao Shao, Mingming Zhang, Hao Wu, Jie Zhang, Can Li, Xuefei Wang, Hongshan Wang, Jing Qin, Yuanyuan Ruan and Jianxin Gu

Int. J. Mol. Sci. 2016, 17(10), 1612; https://doi.org/10.3390/ijms17101612 - 27 Sep 2016

Cited by 7 | Viewed by 5524

Abstract

Calpain-4 belongs to the calpain family of calcium-dependent cysteine proteases, and functions as a small regulatory subunit of the calpains. Recent evidence indicates that calpain-4 plays critical roles in tumor migration and invasion. However, the roles of calpain-4 in gastric tumorigenesis remain poorly [...] Read more.

Calpain-4 belongs to the calpain family of calcium-dependent cysteine proteases, and functions as a small regulatory subunit of the calpains. Recent evidence indicates that calpain-4 plays critical roles in tumor migration and invasion. However, the roles of calpain-4 in gastric tumorigenesis remain poorly understood. Herein, we examined calpain-4 expression by immunohistochemical staining on tissue microarrays containing tumor samples of 174 gastric cancer patients between 2004 and 2008 at a single center. The Kaplan-Meier method was used to compare survival curves, and expression levels were correlated to clinicopathological factors and overall survival. Our data demonstrated that calpain-4 was generally increased in gastric cancer cell lines and primary tumor tissues. High expression of calpain-4 was positively associated with vessel invasion, lymph node metastasis, and advanced TNM (Tumor Node Metastasis) stage. Multivariate analysis identified calpain-4 as an independent prognostic factor for poor prognosis. A predictive nomogram integrating calpain-4 expression with other independent prognosticators was constructed, which generated a better prognostic value for overall survival of gastric cancer patients than a TNM staging system. In conclusion, calpain-4 could be regarded as a potential prognosis indicator for clinical outcomes in gastric cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 3545 KiB

Open AccessArticle

APEH Inhibition Affects Osteosarcoma Cell Viability via Downregulation of the Proteasome

by Rosanna Palumbo, Marta Gogliettino, Ennio Cocca, Roberta Iannitti, Annamaria Sandomenico, Menotti Ruvo, Marco Balestrieri, Mosè Rossi and Gianna Palmieri

Int. J. Mol. Sci. 2016, 17(10), 1614; https://doi.org/10.3390/ijms17101614 - 23 Sep 2016

Cited by 17 | Viewed by 5113

Abstract

The proteasome is a multienzymatic complex that controls the half-life of the majority of intracellular proteins, including those involved in apoptosis and cell-cycle progression. Recently, proteasome inhibition has been shown to be an effective anticancer strategy, although its downregulation is often accompanied by [...] Read more.

The proteasome is a multienzymatic complex that controls the half-life of the majority of intracellular proteins, including those involved in apoptosis and cell-cycle progression. Recently, proteasome inhibition has been shown to be an effective anticancer strategy, although its downregulation is often accompanied by severe undesired side effects. We previously reported that the inhibition of acylpeptide hydrolase (APEH) by the peptide SsCEI 4 can significantly affect the proteasome activity in A375 melanoma or Caco-2 adenocarcinoma cell lines, thus shedding new light on therapeutic strategies based on downstream regulation of proteasome functions. In this work, we investigated the functional correlation between APEH and proteasome in a panel of cancer cell lines, and evaluated the cell proliferation upon SsCEI 4-treatments. Results revealed that SsCEI 4 triggered a proliferative arrest specifically in osteosarcoma U2OS cells via downregulation of the APEH–proteasome system, with the accumulation of the typical hallmarks of proteasome: NF-κB, p21^Waf1, and polyubiquitinylated proteins. We found that the SsCEI 4 anti-proliferative effect involved a senescence-like growth arrest without noticeable cytotoxicity. These findings represent an important step toward understanding the mechanism(s) underlying the APEH-mediated downregulation of proteasome in order to design new molecules able to efficiently regulate the proteasome system for alternative therapeutic strategies. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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12 pages, 1084 KiB

Open AccessArticle

Serum Calcium and the Risk of Breast Cancer: Findings from the Swedish AMORIS Study and a Meta-Analysis of Prospective Studies

by Wahyu Wulaningsih, Harkiran K. Sagoo, Mustafa Hamza, Jennifer Melvin, Lars Holmberg, Hans Garmo, Håkan Malmström, Mats Lambe, Niklas Hammar, Göran Walldius, Ingmar Jungner and Mieke Van Hemelrijck

Int. J. Mol. Sci. 2016, 17(9), 1487; https://doi.org/10.3390/ijms17091487 - 6 Sep 2016

Cited by 31 | Viewed by 6529

Abstract

To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and [...] Read more.

To investigate the association between serum calcium and risk of breast cancer using a large cohort and a systematic review with meta-analysis. From the Swedish Apolipoprotein Mortality Risk (AMORIS) Study we included 229,674 women who had baseline measurements of serum total calcium and albumin. Multivariable Cox regression was used to assess the association between total and albumin-corrected calcium and breast cancer risk. For the systematic review, an electronic search of MEDLINE and EMBASE databases was performed to identify other prospective cohorts assessing the relationship between serum calcium and breast cancer risk. We pooled the results of our AMORIS cohort with other eligible studies in a meta-analysis using a random effects model. I² test was used to assess heterogeneity. In the AMORIS study, 10,863 women were diagnosed with breast cancer (mean follow-up: 19 years). We found an inverse association between total serum calcium and breast cancer when comparing the fourth quartile to the first quartile (HR: 0.94, 95% CI: 0.88–0.99, p value for trend 0.04) and similar results using albumin-corrected calcium. In the systematic review, we identified another two prospective cohorts evaluating pre-diagnostic serum total calcium and breast cancer. Combining these studies and our findings in AMORIS in a meta-analysis showed a protective effect of serum calcium against breast cancer, with a summary RR of 0.80 (95% CI: 0.66–0.97). No substantial heterogeneity was observed. Our findings in AMORIS and the meta-analysis support an inverse association between serum calcium and breast cancer risk, which warrants mechanistic investigations. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 3195 KiB

Open AccessArticle

Cancer-Associated Fibroblasts Modify the Response of Prostate Cancer Cells to Androgen and Anti-Androgens in Three-Dimensional Spheroid Culture

by Theresa Eder, Anja Weber, Hannes Neuwirt, Georg Grünbacher, Christian Ploner, Helmut Klocker, Natalie Sampson and Iris E. Eder

Int. J. Mol. Sci. 2016, 17(9), 1458; https://doi.org/10.3390/ijms17091458 - 1 Sep 2016

Cited by 61 | Viewed by 9642

Abstract

Androgen receptor (AR) targeting remains the gold standard treatment for advanced prostate cancer (PCa); however, treatment resistance remains a major clinical problem. To study the therapeutic effects of clinically used anti-androgens we characterized herein a tissue-mimetic three-dimensional (3D) in vitro model whereby PCa [...] Read more.

Androgen receptor (AR) targeting remains the gold standard treatment for advanced prostate cancer (PCa); however, treatment resistance remains a major clinical problem. To study the therapeutic effects of clinically used anti-androgens we characterized herein a tissue-mimetic three-dimensional (3D) in vitro model whereby PCa cells were cultured alone or with PCa-associated fibroblasts (CAFs). Notably, the ratio of PCa cells to CAFs significantly increased in time in favor of the tumor cells within the spheroids strongly mimicking PCa in vivo. Despite this loss of CAFs, the stromal cells, which were not sensitive to androgen and even stimulated by the anti-androgens, significantly influenced the sensitivity of PCa cells to androgen and to the anti-androgens bicalutamide and enzalutamide. In particular, DuCaP cells lost sensitivity to enzalutamide when co-cultured with CAFs. In LAPC4/CAF and LNCaP/CAF co-culture spheroids the impact of the CAFs was less pronounced. In addition, 3D spheroids exhibited a significant increase in E-cadherin and substantial expression of vimentin in co-culture spheroids, whereas AR levels remained unchanged or even decreased. In LNCaP/CAF spheroids we further found increased Akt signaling that could be inhibited by the phosphatidyl-inositol 3 kinase (PI3K) inhibitor LY294002, thereby overcoming the anti-androgen resistance of the spheroids. Our data show that CAFs influence drug response of PCa cells with varying impact and further suggest this spheroid model is a valuable in vitro drug testing tool. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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13 pages, 2548 KiB

Open AccessArticle

Human TRIB2 Oscillates during the Cell Cycle and Promotes Ubiquitination and Degradation of CDC25C

by Kai Ling Liang, Roberto Paredes, Ruaidhri Carmody, Patrick A. Eyers, Stefan Meyer, Tommie V. McCarthy and Karen Keeshan

Int. J. Mol. Sci. 2016, 17(9), 1378; https://doi.org/10.3390/ijms17091378 - 23 Aug 2016

Cited by 18 | Viewed by 7930

Abstract

Tribbles homolog 2 (TRIB2) is a member of the mammalian Tribbles family of serine/threonine pseudokinases (TRIB1-3). Studies of TRIB2 indicate that many of the molecular interactions between the single Drosophila Tribbles (Trbl) protein and interacting partners are evolutionary conserved. In this study, we [...] Read more.

Tribbles homolog 2 (TRIB2) is a member of the mammalian Tribbles family of serine/threonine pseudokinases (TRIB1-3). Studies of TRIB2 indicate that many of the molecular interactions between the single Drosophila Tribbles (Trbl) protein and interacting partners are evolutionary conserved. In this study, we examined the relationship between TRIB2 and cell division cycle 25 (CDC25) family of dual-specificity protein phosphatases (mammalian homologues of Drosophila String), which are key physiological cell cycle regulators. Using co-immunoprecipitation we demonstrate that TRIB2 interacts with CDC25B and CDC25C selectively. Forced overexpression of TRIB2 caused a marked decrease in total CDC25C protein levels. Following inhibition of the proteasome, CDC25C was stabilized in the nuclear compartment. This implicates TRIB2 as a regulator of nuclear CDC25C turnover. In complementary ubiquitination assays, we show that TRIB2-mediated degradation of CDC25C is associated with lysine-48-linked CDC25C polyubiquitination driven by the TRIB2 kinase-like domain. A cell cycle associated role for TRIB2 is further supported by the cell cycle regulated expression of TRIB2 protein levels. Our findings reveal mitotic CDC25C as a new target of TRIB2 that is degraded via the ubiquitin proteasome system. Inappropriate CDC25C regulation could mechanistically underlie TRIB2 mediated regulation of cellular proliferation in neoplastic cells. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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0 pages, 2320 KiB

Open AccessArticle

RETRACTED: Advanced Glycation End-Products Enhance Lung Cancer Cell Invasion and Migration

by Te-Chun Hsia, Mei-Chin Yin and Mei-Chin Mong

Int. J. Mol. Sci. 2016, 17(8), 1289; https://doi.org/10.3390/ijms17081289 - 9 Aug 2016

Cited by 10 | Viewed by 6610 | Retraction

Abstract

Effects of carboxymethyllysine (CML) and pentosidine, two advanced glycation end-products (AGEs), upon invasion and migration in A549 and Calu-6 cells, two non-small cell lung cancer (NSCLC) cell lines were examined. CML or pentosidine at 1, 2, 4, 8 or 16 μmol/L were added [...] Read more.

Effects of carboxymethyllysine (CML) and pentosidine, two advanced glycation end-products (AGEs), upon invasion and migration in A549 and Calu-6 cells, two non-small cell lung cancer (NSCLC) cell lines were examined. CML or pentosidine at 1, 2, 4, 8 or 16 μmol/L were added into cells. Proliferation, invasion and migration were measured. CML or pentosidine at 4–16 μmol/L promoted invasion and migration in both cell lines, and increased the production of reactive oxygen species, tumor necrosis factor-α, interleukin-6 and transforming growth factor-β1. CML or pentosidine at 2–16 μmol/L up-regulated the protein expression of AGE receptor, p47^phox, intercellular adhesion molecule-1 and fibronectin in test NSCLC cells. Matrix metalloproteinase-2 protein expression in A549 and Calu-6 cells was increased by CML or pentosidine at 4–16 μmol/L. These two AGEs at 2–16 μmol/L enhanced nuclear factor κ-B (NF-κ B) p65 protein expression and p38 phosphorylation in A549 cells. However, CML or pentosidine at 4–16 μmol/L up-regulated NF-κB p65 and p-p38 protein expression in Calu-6 cells. These findings suggest that CML and pentosidine, by promoting the invasion, migration and production of associated factors, benefit NSCLC metastasis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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11 pages, 831 KiB

Open AccessArticle

MicroRNA-31 Emerges as a Predictive Biomarker of Pathological Response and Outcome in Locally Advanced Rectal Cancer

by Cristina Caramés, Ion Cristobal, Víctor Moreno, Juan P. Marín, Paula González-Alonso, Blanca Torrejón, Pablo Minguez, Ana Leon, José I. Martín, Roberto Hernández, Manuel Pedregal, María J. Martín, Delia Cortés, Damian García-Olmo, María J. Fernández, Federico Rojo and Jesús García-Foncillas

Int. J. Mol. Sci. 2016, 17(6), 878; https://doi.org/10.3390/ijms17060878 - 3 Jun 2016

Cited by 30 | Viewed by 6200

Abstract

Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision has emerged as the standard treatment for locally advanced rectal cancer (LARC) patients. However, many cases do not respond to neoadjuvant CRT, suffering unnecessary toxicities and surgery delays. Thus, identification of predictive biomarkers for neoadjuvant [...] Read more.

Neoadjuvant chemoradiotherapy (CRT) followed by total mesorectal excision has emerged as the standard treatment for locally advanced rectal cancer (LARC) patients. However, many cases do not respond to neoadjuvant CRT, suffering unnecessary toxicities and surgery delays. Thus, identification of predictive biomarkers for neoadjuvant CRT is a current clinical need. In the present study, microRNA-31 expression was measured in formalin-fixed paraffin-embedded (FFPE) biopsies from 78 patients diagnosed with LARC who were treated with neoadjuvant CRT. Then, the obtained results were correlated with clinical and pathological characteristics and outcome. High microRNA-31 (miR-31) levels were found overexpressed in 34.2% of cases. Its overexpression significantly predicted poor pathological response (p = 0.018) and worse overall survival (OS) (p = 0.008). The odds ratio for no pathological response among patients with miR-31 overexpression was 0.18 (Confidence Interval = 0.06 to 0.57; p = 0.003). Multivariate analysis corroborated the clinical impact of miR-31 in determining pathological response to neoadjuvant CRT as well as OS. Altogether, miR-31 quantification emerges as a novel valuable clinical tool to predict both pathological response and outcome in LARC patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 6948 KiB

Open AccessArticle

Inhibition of REST Suppresses Proliferation and Migration in Glioblastoma Cells

by Dianbao Zhang, Ying Li, Rui Wang, Yunna Li, Ping Shi, Zhoumi Kan and Xining Pang

Int. J. Mol. Sci. 2016, 17(5), 664; https://doi.org/10.3390/ijms17050664 - 3 May 2016

Cited by 42 | Viewed by 7950

Abstract

Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of [...] Read more.

Glioblastoma (GBM) is the most common primary brain tumor, with poor prognosis and a lack of effective therapeutic options. The aberrant expression of transcription factor REST (repressor element 1-silencing transcription factor) had been reported in different kinds of tumors. However, the function of REST and its mechanisms in GBM remain elusive. Here, REST expression was inhibited by siRNA silencing in U-87 and U-251 GBM cells. Then CCK-8 assay showed significantly decreased cell proliferation, and the inhibition of migration was verified by scratch wound healing assay and transwell assay. Using cell cycle analysis and Annexin V/PI straining assay, G1 phase cell cycle arrest was found to be a reason for the suppression of cell proliferation and migration upon REST silencing, while apoptosis was not affected by REST silencing. Further, the detection of REST-downstream genes involved in cytostasis and migration inhibition demonstrated that CCND1 and CCNE1 were reduced; CDK5R1, BBC3, EGR1, SLC25A4, PDCD7, MAPK11, MAPK12, FADD and DAXX were enhanced, among which BBC3 and DAXX were direct targets of REST, as verified by ChIP (chromatin immunoprecipitation) and Western blotting. These data suggested that REST is a master regulator that maintains GBM cells proliferation and migration, partly through regulating cell cycle by repressing downstream genes, which might represent a potential target for GBM therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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17 pages, 1607 KiB

Open AccessArticle

Identification of 42 Genes Linked to Stage II Colorectal Cancer Metastatic Relapse

by Rabeah A. Al-Temaimi, Tuan Zea Tan, Makia J. Marafie, Jean Paul Thiery, Philip Quirke and Fahd Al-Mulla

Int. J. Mol. Sci. 2016, 17(5), 598; https://doi.org/10.3390/ijms17050598 - 28 Apr 2016

Cited by 13 | Viewed by 7055

Abstract

Colorectal cancer (CRC) is one of the leading causes of cancer mortality. Metastasis remains the primary cause of CRC death. Predicting the possibility of metastatic relapse in early-stage CRC is of paramount importance to target therapy for patients who really need it and [...] Read more.

Colorectal cancer (CRC) is one of the leading causes of cancer mortality. Metastasis remains the primary cause of CRC death. Predicting the possibility of metastatic relapse in early-stage CRC is of paramount importance to target therapy for patients who really need it and spare those with low-potential of metastasis. Ninety-six stage II CRC cases were stratified using high-resolution array comparative genomic hybridization (aCGH) data based on a predictive survival algorithm and supervised clustering. All genes included within the resultant copy number aberrations were each interrogated independently at mRNA level using CRC expression datasets available from public repositories, which included 1820 colon cancers, and 167 normal colon tissues. Reduced mRNA expression driven by copy number losses and increased expression driven by copy number gains revealed 42 altered transcripts (29 reduced and 13 increased transcripts) associated with metastatic relapse, short disease-free or overall survival, and/or epithelial to mesenchymal transition (EMT). Resultant genes were classified based on gene ontology (GO), which identified four functional enrichment groups involved in growth regulation, genomic integrity, metabolism, and signal transduction pathways. The identified 42 genes may be useful for predicting metastatic relapse in stage II CRC. Further studies are necessary to validate these findings. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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7 pages, 2379 KiB

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KRAS/BRAF Analysis in Ovarian Low-Grade Serous Carcinoma Having Synchronous All Pathological Precursor Regions

by Kohei Nakamura, Kentaro Nakayama, Tomoka Ishibashi, Noriyoshi Ishikawa, Masako Ishikawa, Hiroshi Katagiri, Toshiko Minamoto, Emi Sato, Kaori Sanuki, Hitomi Yamashita, Kouji Iida, Razia Sultana and Satoru Kyo

Int. J. Mol. Sci. 2016, 17(5), 625; https://doi.org/10.3390/ijms17050625 - 26 Apr 2016

Cited by 11 | Viewed by 8588

Abstract

Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains [...] Read more.

Ovarian low-grade serous carcinoma is thought to begin as a serous cystadenoma or adenofibroma that progresses in a slow stepwise fashion. Among the low-grade serous carcinomas, there is a high frequency of activating mutations in the KRAS or BRAF genes; however, it remains unclear as to how these mutations contribute to tumor progression. This is the first report to track the histopathological progression of serous adenofibroma to low-grade serous carcinoma. Each stage was individually analyzed by pathological and molecular genetic methods to determine what differences occur between the distinct stages of progression. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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13 pages, 1384 KiB

Open AccessArticle

Significance of Matrix Metalloproteinase 9 Expression as Supporting Marker to Cytokeratin 19 mRNA in Sentinel Lymph Nodes in Breast Cancer Patients

by Marek Murawski, Marta Woźniak, Kamila Duś-Szachniewicz, Paweł Kołodziej, Marta Rzeszutko and Piotr Ziółkowski

Int. J. Mol. Sci. 2016, 17(4), 571; https://doi.org/10.3390/ijms17040571 - 21 Apr 2016

Cited by 3 | Viewed by 5800

Abstract

One-step nucleic acid amplification (OSNA) detects and quantifies, with the use of a polymerase chain reaction, the presence of cytokeratin 19 mRNA in sentinel lymph nodes. The main advantage of the OSNA assay is the avoidance of second surgery in case of positive [...] Read more.

One-step nucleic acid amplification (OSNA) detects and quantifies, with the use of a polymerase chain reaction, the presence of cytokeratin 19 mRNA in sentinel lymph nodes. The main advantage of the OSNA assay is the avoidance of second surgery in case of positive sentinel lymph node diagnosis. The objective of this study was to evaluate the significance of matrix metalloproteinase 9 expression by immunohistochemistry as supporting marker to cytokeratin 19 mRNA in sentinel lymph nodes in breast cancer patients and to relate this expression with clinicopathological data. This study was conducted on fresh sentinel lymph nodes obtained from 40 patients with tumors classified as carcinoma of no special type. The presence of metastatic cells in the slices of lymph nodes was evaluated by immunohistochemistry using antibodies for CK19 and MMP-9. Expression of CK19 and MMP-9 in lymph nodes was also confirmed by means of Western blot analysis. Results indicated that the strongest correlation with CK19 mRNA was displayed by MMP-9, CK19 (by immunohistochemistry, IHC), and nodal metastases (p < 0.001). Higher histological grading also positively correlated with CK19 mRNA, however that correlation was less significant. Since MMP-9 shows very strong correlation with CK19 mRNA in breast carcinoma of no special type metastases, expression of MMP-9 in sentinel lymph nodes should be considered as useful method whenever OSNA analysis is not available. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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12 pages, 1445 KiB

Open AccessArticle

Wnt9A Induction Linked to Suppression of Human Colorectal Cancer Cell Proliferation

by Irshad Ali, Bani Medegan and Donald P. Braun

Int. J. Mol. Sci. 2016, 17(4), 495; https://doi.org/10.3390/ijms17040495 - 2 Apr 2016

Cited by 20 | Viewed by 7788

Abstract

Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding [...] Read more.

Most studies of Wnt signaling in malignant tissues have focused on the canonical Wnt pathway (CWP) due to its role in stimulating cellular proliferation. The role of the non-canonical Wnt pathway (NCWP) in tissues with dysregulated Wnt signaling is not fully understood. Understanding NCWP’s role is important since these opposing pathways act in concert to maintain homeostasis in healthy tissues. Our preliminary studies demonstrated that LiCl inhibited proliferation of primary cells derived from colorectal cancer (CRC). Since LiCl stimulates cell proliferation in normal tissues and NCWP suppresses it, the present study was designed to investigate the impact of NCWP components in LiCl-mediated effects. LiCl-mediated inhibition of CRC cell proliferation (p < 0.001) and increased apoptosis (p < 0.01) coincided with 23-fold increase (p < 0.025) in the expression of the NCWP ligand, Wnt9A. LiCl also suppressed β-catenin mRNA (p < 0.03), total β-catenin protein (p < 0.025) and the active form of β-catenin. LiCl-mediated inhibition of CRC cell proliferation was partially reversed by IWP-2, and Wnt9A antibody. Recombinant Wnt9A protein emulated LiCl effects by suppressing β-catenin protein (p < 0.001), inhibiting proliferation (p < 0.001) and increasing apoptosis (p < 0.03). This is the first study to demonstrate induction of a NCWP ligand, Wnt9A as part of a mechanism for LiCl-mediated suppression of CRC cell proliferation. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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13 pages, 3832 KiB

Open AccessArticle

Overexpression of TRPV3 Correlates with Tumor Progression in Non-Small Cell Lung Cancer

by Xiaolei Li, Qianhui Zhang, Kai Fan, Baiyan Li, Huifeng Li, Hanping Qi, Jing Guo, Yonggang Cao and Hongli Sun

Int. J. Mol. Sci. 2016, 17(4), 437; https://doi.org/10.3390/ijms17040437 - 24 Mar 2016

Cited by 61 | Viewed by 7245

Abstract

(1) Background: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca²⁺-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance [...] Read more.

(1) Background: Transient receptor potential vanilloid 3 (TRPV3) is a member of the TRP channels family of Ca²⁺-permeant channels. The proteins of some TRP channels are highly expressed in cancer cells. This study aimed to assess the clinical significance and biological functions of TRPV3 in non-small cell lung cancer (NSCLC); (2) Methods: Immunohistochemistry was used to detect the expression of TRPV3 in NSCLC tissues and adjacent noncancerous lung tissues. Western blot was used to detect the protein expressions of TRPV3, CaMKII, p-CaMKII, CyclinA, CyclinD, CyclinE1, CDK2, CDK4, and P27. Small interfering RNA was used to deplete TRPV3 expression. A laser scanning confocal microscope was used to measure intracellular calcium concentration ([Ca²⁺]_i). Flow cytometry was used to analyze cell cycle; (3) Results: TRPV3 was overexpressed in 65 of 96 (67.7%) human lung cancer cases and correlated with differentiation (p = 0.001) and TNM stage (p = 0.004). Importantly, TRPV3 expression was associated with short overall survival. In addition, blocking or knockdown of TRPV3 could inhibit lung cancer cell proliferation. Moreover, TRPV3 inhibition could decrease [Ca²⁺]_i of lung cancer cells and arrest cell cycle at the G1/S boundary. Further results revealed that TRPV3 inhibition decreased expressions of p-CaMKII, CyclinA, CyclinD1, CyclinE, and increased P27 level; (4) Conclusions: Our findings demonstrate that TRPV3 was overexpressed in NSCLC and correlated with lung cancer progression. TRPV3 activation could promote proliferation of lung cancer cells. TRPV3 might serve as a potential companion drug target in NSCLC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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12 pages, 3958 KiB

Open AccessArticle

Tamoxifen Treatment of Breast Cancer Cells: Impact on Hedgehog/GLI1 Signaling

by Victoria E. Villegas, Milena Rondón-Lagos, Laura Annaratone, Isabella Castellano, Adriana Grismaldo, Anna Sapino and Peter G. Zaphiropoulos

Int. J. Mol. Sci. 2016, 17(3), 308; https://doi.org/10.3390/ijms17030308 - 27 Feb 2016

Cited by 25 | Viewed by 6976

Abstract

The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, [...] Read more.

The selective estrogen receptor (ER) modulator tamoxifen (TAM) has become the standard therapy for the treatment of ER+ breast cancer patients. Despite the obvious benefits of TAM, a proportion of patients acquire resistance to treatment, and this is a significant clinical problem. Consequently, the identification of possible mechanisms involved in TAM-resistance should help the development of new therapeutic targets. In this study, we present in vitro data using a panel of different breast cancer cell lines and demonstrate the modulatory effect of TAM on cellular proliferation and expression of Hedgehog signaling components, including the terminal effector of the pathway, the transcription factor GLI1. A variable pattern of expression following TAM administration was observed, reflecting the distinctive properties of the ER+ and ER− cell lines analyzed. Remarkably, the TAM-induced increase in the proliferation of the ER+ ZR-75-1 and BT474 cells parallels a sustained upregulation of GLI1 expression and its translocation to the nucleus. These findings, implicating a TAM-GLI1 signaling cross-talk, could ultimately be exploited not only as a means for novel prognostication markers but also in efforts to effectively target breast cancer subtypes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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10 pages, 420 KiB

Open AccessCommunication

Using Copy Number Alterations to Identify New Therapeutic Targets for Bladder Carcinoma

by Donatella Conconi, Elena Sala, Giorgio Bovo, Guido Strada, Leda Dalprà, Marialuisa Lavitrano and Angela Bentivegna

Int. J. Mol. Sci. 2016, 17(3), 271; https://doi.org/10.3390/ijms17030271 - 24 Feb 2016

Cited by 11 | Viewed by 5415

Abstract

Bladder cancer represents the ninth most widespread malignancy throughout the world. It is characterized by the presence of two different clinical and prognostic subtypes: non-muscle-invasive bladder cancers (NMIBCs) and muscle-invasive bladder cancers (MIBCs). MIBCs have a poor outcome with a common progression to [...] Read more.

Bladder cancer represents the ninth most widespread malignancy throughout the world. It is characterized by the presence of two different clinical and prognostic subtypes: non-muscle-invasive bladder cancers (NMIBCs) and muscle-invasive bladder cancers (MIBCs). MIBCs have a poor outcome with a common progression to metastasis. Despite improvements in knowledge, treatment has not advanced significantly in recent years, with the absence of new therapeutic targets. Because of the limitations of current therapeutic options, the greater challenge will be to identify biomarkers for clinical application. For this reason, we compared our array comparative genomic hybridization (array-CGH) results with those reported in literature for invasive bladder tumors and, in particular, we focused on the evaluation of copy number alterations (CNAs) present in biopsies and retained in the corresponding cancer stem cell (CSC) subpopulations that should be the main target of therapy. According to our data, CCNE1, MYC, MDM2 and PPARG genes could be interesting therapeutic targets for bladder CSC subpopulations. Surprisingly, HER2 copy number gains are not retained in bladder CSCs, making the gene-targeted therapy less interesting than the others. These results provide precious advice for further study on bladder therapy; however, the clinical importance of these results should be explored. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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17 pages, 2705 KiB

Open AccessArticle

Generation of Potent Anti-Vascular Endothelial Growth Factor Neutralizing Antibodies from Mouse Phage Display Library for Cancer Therapy

by Yan-Da Lai, Yen-Yu Wu, Yi-Jiue Tsai, Yi-San Tsai, Yu-Ying Lin, Szu-Liang Lai, Chao-Yang Huang, Ying-Yung Lok, Chih-Yung Hu and Jiann-Shiun Lai

Int. J. Mol. Sci. 2016, 17(2), 214; https://doi.org/10.3390/ijms17020214 - 5 Feb 2016

Cited by 13 | Viewed by 7340

Abstract

Vascular endothelial growth factor (VEGF) is an important stimulator for angiogenesis in solid tumors. Blocking VEGF activity is an effective therapeutic strategy to inhibit tumor growth and metastasis. Avastin, a humanized monoclonal antibody recognizes VEGF, has been approved by the US Food and [...] Read more.

Vascular endothelial growth factor (VEGF) is an important stimulator for angiogenesis in solid tumors. Blocking VEGF activity is an effective therapeutic strategy to inhibit tumor growth and metastasis. Avastin, a humanized monoclonal antibody recognizes VEGF, has been approved by the US Food and Drug Administration. To generate potential VEGF-recognizing antibodies with better tumor regression ability than that of Avastin, we have designed a systematic antibody selection plan. From mice immunized with recombinant human VEGF, we generated three phage display libraries, scFv-M13KO7, Fab-M13KO7, and scFv-Hyperphage, in single-chain Fv (scFv) or Fab format, displayed using either M13KO7 helper phage or Hyperphage. Solid-phase and solution-phase selection strategies were then applied to each library, generating six panning combinations. A total of sixty-four antibodies recognizing VEGF were obtained. Based on the results of epitope mapping, binding affinity, and biological functions in tumor inhibition, eight antibodies were chosen to examine their abilities in tumor regression in a mouse xenograft model using human COLO 205 cancer cells. Three of them showed improvement in the inhibition of tumor growth (328%–347% tumor growth ratio (% of Day 0 tumor volume) on Day 21 vs. 435% with Avastin). This finding suggests a potential use of these three antibodies for VEGF-targeted therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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9 pages, 979 KiB

Open AccessArticle

Histone Methylation Marks on Circulating Nucleosomes as Novel Blood-Based Biomarker in Colorectal Cancer

by Ugur Gezer, Ebru E. Yörüker, Metin Keskin, Cemil Burak Kulle, Yoganiranjana Dharuman and Stefan Holdenrieder

Int. J. Mol. Sci. 2015, 16(12), 29654-29662; https://doi.org/10.3390/ijms161226180 - 11 Dec 2015

Cited by 69 | Viewed by 7995

Abstract

Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer as potential non-invasive biomarkers, as stable structure in circulation nucleosomes could be valuable sources for detection of cancer-specific alterations in histone modifications. Our interest is in histone methylation marks with [...] Read more.

Circulating nucleic acids (CNAs) are under investigation as a liquid biopsy in cancer as potential non-invasive biomarkers, as stable structure in circulation nucleosomes could be valuable sources for detection of cancer-specific alterations in histone modifications. Our interest is in histone methylation marks with a focus on colorectal cancer, one of the leading cancers respective the incidence and mortality. Our previous work included the analysis of trimethylations of lysine 9 on histone 3 (H3K9me3) and of lysine 20 on histone 4 (H4K20me3) by chromatin immuno- precipitation-related PCR in circulating nucleosomes. Here we asked whether global immunologic measurement of histone marks in circulation could be a suitable approach to show their potential as biomarkers. In addition to H3K9me3 and H4K20me3 we also measured H3K27me3 in plasma samples from CRC patients (n = 63) and cancer free individuals (n = 40) by ELISA-based methylation assays. Our results show that of three marks, the amounts of H3K27me3 (p = 0.04) and H4K20me3 (p < 0.001) were significantly lower in CRC patients than in healthy controls. For H3K9me3 similar amounts were measured in both groups. Areas under the curve (AUC) in receiver operating characteristic (ROC) curves indicating the power of CRC detection were 0.620 for H3K27me3, 0.715 for H4K20me3 and 0.769 for the combination of both markers. In conclusion, findings of this preliminary study reveal the potential of blood-based detection of CRC by quantification of histone methylation marks and the additive effect of the marker combination. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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12 pages, 948 KiB

Open AccessArticle

Simultaneous Analysis of SEPT9 Promoter Methylation Status, Micronuclei Frequency, and Folate-Related Gene Polymorphisms: The Potential for a Novel Blood-Based Colorectal Cancer Biomarker

by Gloria Ravegnini, Juan Manuel Zolezzi Moraga, Francesca Maffei, Muriel Musti, Corrado Zenesini, Vittorio Simeon, Giulia Sammarini, Davide Festi, Patrizia Hrelia and Sabrina Angelini

Int. J. Mol. Sci. 2015, 16(12), 28486-28497; https://doi.org/10.3390/ijms161226113 - 1 Dec 2015

Cited by 22 | Viewed by 7311

Abstract

One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects’ positive fecal occult blood test (FOBT). In order to [...] Read more.

One challenge in colorectal cancer (CRC) is identifying novel biomarkers to be introduced in screening programs. The present study investigated the promoter methylation status of the SEPT9 gene in peripheral blood samples of subjects’ positive fecal occult blood test (FOBT). In order to add new insights, we investigated the association between SEPT9 promoter methylation and micronuclei frequency, and polymorphisms in the folate-related pathway genes. SEPT9 promoter methylation, micronuclei frequency, and genotypes were evaluated on 74 individuals’ FOBT positive. Individuals were subjected to a colonoscopy that provided written informed consent for study participation. SEPT9 promoter methylation status was significantly lower in the CRC group than controls (p = 0.0006). In contrast, the CaCo2 cell-line, analyzed as a tissue specific model of colon adenocarcinoma, showed a significantly higher percentage of SEPT9 promoter methylation compared to the CRC group (p < 0.0001). Linear regression analysis showed an inverse correlation between micronuclei frequency and the decrease in the methylation levels of SEPT9 promoter region among CRC patients (β = −0.926, p = 0.0001). With regard to genotype analysis, we showed the involvement of the DHFR polymorphism (rs70991108) in SEPT9 promoter methylation level in CRC patients only. In particular, the presence of at least one 19 bp del allele significantly correlates with decreased SEPT9 promoter methylation, compared to the 19 bp ins/ins genotype (p = 0.007). While remaining aware of the strengths and limitations of the study, this represents the first evidence of a novel approach for the early detection of CRC, using SEPT9 promoter methylation, micronuclei frequency and genotypes, with the potential to improve CRC risk assessment. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 1257 KiB

Open AccessArticle

The Importance of Caveolin-1 as Key-Regulator of Three-Dimensional Growth in Thyroid Cancer Cells Cultured under Real and Simulated Microgravity Conditions

by Stefan Riwaldt, Johann Bauer, Jessica Pietsch, Markus Braun, Jürgen Segerer, Achim Schwarzwälder, Thomas J. Corydon, Manfred Infanger and Daniela Grimm

Int. J. Mol. Sci. 2015, 16(12), 28296-28310; https://doi.org/10.3390/ijms161226108 - 30 Nov 2015

Cited by 41 | Viewed by 7825

Abstract

We recently demonstrated that the CAV1 gene was down-regulated, when poorly differentiated thyroid FTC-133 cancer cells formed spheroids under simulated microgravity conditions. Here, we present evidence that the caveolin-1 protein is involved in the inhibition of spheroid formation, when confluent monolayers are exposed [...] Read more.

We recently demonstrated that the CAV1 gene was down-regulated, when poorly differentiated thyroid FTC-133 cancer cells formed spheroids under simulated microgravity conditions. Here, we present evidence that the caveolin-1 protein is involved in the inhibition of spheroid formation, when confluent monolayers are exposed to microgravity. The evidence is based on proteins detected in cells and their supernatants of the recent spaceflight experiment: “NanoRacks-CellBox-Thyroid Cancer”. The culture supernatant had been collected in a special container adjacent to the flight hardware incubation chamber and stored at low temperature until it was analyzed by Multi-Analyte Profiling (MAP) technology, while the cells remaining in the incubation chamber were fixed by RNAlater and examined by mass spectrometry. The soluble proteins identified by MAP were investigated in regard to their mutual interactions and their influence on proteins, which were associated with the cells secreting the soluble proteins and had been identified in a preceding study. A Pathway Studio v.11 analysis of the soluble and cell-associated proteins together with protein kinase C alpha (PRKCA) suggests that caveolin-1 is involved, when plasminogen enriched in the extracellular space is not activated and the vascular cellular adhesion molecule (VCAM-1) mediated cell–cell adhesion is simultaneously strengthened and activated PRKCA is recruited in caveolae, while the thyroid cancer cells do not form spheroids. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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13 pages, 6385 KiB

Open AccessArticle

Silencing of Kv1.5 Gene Inhibits Proliferation and Induces Apoptosis of Osteosarcoma Cells

by Jin Wu, Zhida Chen, Qingjun Liu, Wenrong Zeng, Xinyu Wu and Bin Lin

Int. J. Mol. Sci. 2015, 16(11), 26914-26926; https://doi.org/10.3390/ijms161126002 - 11 Nov 2015

Cited by 26 | Viewed by 6237

Abstract

Kv1.5 (also known as KCNA5) is a protein encoded by the KCNA5 gene, which belongs to the voltage-gated potassium channel, shaker-related subfamily. Recently, a number of studies have suggested that Kv1.5 is overexpressed in numerous cancers and plays crucial roles in cancer development. [...] Read more.

Kv1.5 (also known as KCNA5) is a protein encoded by the KCNA5 gene, which belongs to the voltage-gated potassium channel, shaker-related subfamily. Recently, a number of studies have suggested that Kv1.5 is overexpressed in numerous cancers and plays crucial roles in cancer development. However, until now, the expression and functions of Kv1.5 in osteosarcoma are still unclear. To characterize the potential biological functions of Kv1.5 in osteosarcoma, herein, we examined the expression levels of Kv1.5 in osteosarcoma cells and tissues using quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry assays. Four short hairpin RNAs (shRNAs) targeting Kv1.5 were designed and homologous recombination technology was used to construct pGeneSil-Kv1.5 vectors. In addition, the vectors were transfected into osteosarcoma MG63 cells and Kv1.5 mRNA level was measured by qRT-PCR and the Kv1.5 protein level was examined by western blot. We also examined the effects of Kv1.5 silencing on proliferation, cell cycle and apoptosis of the osteosarcoma cells using CCK-8, colony formation, flow cytometry and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays. Our results showed that Kv1.5 was aberrantly expressed in osteosarcoma and that the synthesized shRNA targeting Kv1.5 reduced Kv1.5 mRNA and protein expression effectively. Silencing Kv1.5 expression in the osteosarcoma cells significantly inhibited the proliferation of osteosarcoma cells, induced cell cycle arrest at G0/G1 phase, and induced cell apoptosis through up-regulation of p21, p27, Bax, Bcl-XL and caspase-3 and down-regulation of cyclins A, cyclins D1, cyclins E, Bcl-2 and Bik. In summary, our results indicate that Kv1.5 silencing could suppress osteosarcoma progression through multiple signaling pathways and suggest that Kv1.5 may be a novel target for osteosarcoma therapeutics. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 7619 KiB

Open AccessArticle

Mobilization of Copper ions by Flavonoids in Human Peripheral Lymphocytes Leads to Oxidative DNA Breakage: A Structure Activity Study

by Hussain Arif, Nida Rehmani, Mohd Farhan, Aamir Ahmad and Sheikh Mumtaz Hadi

Int. J. Mol. Sci. 2015, 16(11), 26754-26769; https://doi.org/10.3390/ijms161125992 - 9 Nov 2015

Cited by 45 | Viewed by 7984

Abstract

Epidemiological studies have linked dietary consumption of plant polyphenols with lower incidence of various cancers. In particular, flavonoids (present in onion, tomato and other plant sources) induce apoptosis and cytotoxicity in cancer cells. These can therefore be used as lead compounds for the [...] Read more.

Epidemiological studies have linked dietary consumption of plant polyphenols with lower incidence of various cancers. In particular, flavonoids (present in onion, tomato and other plant sources) induce apoptosis and cytotoxicity in cancer cells. These can therefore be used as lead compounds for the synthesis of novel anticancer drugs with greater bioavailability. In the present study, we examined the chemical basis of cytotoxicity of flavonoids by studying the structure–activity relationship of myricetin (MN), fisetin (FN), quercetin (QN), kaempferol (KL) and galangin (GN). Using single cell alkaline gel electrophoresis (comet assay), we established the relative efficiency of cellular DNA breakage as MN > FN > QN > KL > GN. Also, we determined that the cellular DNA breakage was the result of mobilization of chromatin-bound copper ions and the generation of reactive oxygen species. The relative DNA binding affinity order was further confirmed using molecular docking and thermodynamic studies through the interaction of flavonoids with calf thymus DNA. Our results suggest that novel anti-cancer molecules should have ortho-dihydroxy groups in B-ring and hydroxyl groups at positions 3 and 5 in the A-ring system. Additional hydroxyl groups at other positions further enhance the cellular cytotoxicity of the flavonoids. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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20 pages, 4224 KiB

Open AccessArticle

Nimbolide Induces ROS-Regulated Apoptosis and Inhibits Cell Migration in Osteosarcoma

by Ju-Fang Liu, Chun-Han Hou, Feng-Ling Lin, Ya-Ting Tsao and Sheng-Mou Hou

Int. J. Mol. Sci. 2015, 16(10), 23405-23424; https://doi.org/10.3390/ijms161023405 - 29 Sep 2015

Cited by 42 | Viewed by 7679

Abstract

Osteosarcoma (OS) is a primary malignant tumor of bone and is most prevalent in children and adolescents. OS is frequently associated with pulmonary metastasis, which is the main cause of OS-related mortality. OS has a poor prognosis and is often unresponsive to conventional [...] Read more.

Osteosarcoma (OS) is a primary malignant tumor of bone and is most prevalent in children and adolescents. OS is frequently associated with pulmonary metastasis, which is the main cause of OS-related mortality. OS has a poor prognosis and is often unresponsive to conventional chemotherapy. In this study, we determined that Nimbolide, a novel anti-cancer therapy, acts by modulating multiple mechanisms in osteosarcoma cells. Nimbolide induces apoptosis by increasing endoplasmic reticulum (ER) stress, mitochondrial dysfunction, accumulation of reactive oxygen species (ROS), and finally, caspase activation. We also determined that Nimbolide inhibits cell migration, which is crucial for metastasis, by reducing the expression of integrin αvβ5. In addition, our results demonstrate that integrin αvβ5 expression is modulated by the PI3K/Akt and NF-κB signaling cascade. Nimbolide has potential as an anti-tumor drug given its multifunctional effects in OS. Collectively, these results help us to understand the mechanisms of action of Nimbolide and will aid in the development of effective therapies for OS. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 21991 KiB

Open AccessArticle

Selection and Characterization of Single Chain Antibody Fragments Specific for Hsp90 as a Potential Cancer Targeting Molecule

by Edyta Petters, Aleksandra Sokolowska-Wedzina and Jacek Otlewski

Int. J. Mol. Sci. 2015, 16(8), 19920-19935; https://doi.org/10.3390/ijms160819920 - 21 Aug 2015

Cited by 4 | Viewed by 7167

Abstract

Heat shock proteins play an essential role in facilitating malignant transformation and they have been recognized as important factors in human cancers. One of the key elements of the molecular chaperones machinery is Hsp90 and it has recently become a target for anticancer [...] Read more.

Heat shock proteins play an essential role in facilitating malignant transformation and they have been recognized as important factors in human cancers. One of the key elements of the molecular chaperones machinery is Hsp90 and it has recently become a target for anticancer therapeutic approaches. The potential and importance of Hsp90-directed agents becomes apparent when one realizes that disruption of Hsp90 function may influence over 200 oncogenic client proteins. Here, we described the selection and characterization of Hsp90-specific antibody fragments from commercially available Tomlinson I and J phage display libraries. The affinities of Hsp90-binding scFv variants were measured using SPR method. Then, based on the best clone selected, we performed the affinity maturation procedure and obtained valuable Hsp90-specific clones. The selected binders were expressed and applied for immunostaining, ELISA and SPR analysis using model cancer cell lines. All performed experiments confirmed the ability of selected antibodies to interact with the Hsp90. Therefore, the presented Hsp90-specific scFv, might be a starting point for the development of a novel antibody-based strategy targeting cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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11 pages, 830 KiB

Open AccessCommunication

Pyrosequencing-Based Assays for Rapid Detection of HER2 and HER3 Mutations in Clinical Samples Uncover an E332E Mutation Affecting HER3 in Retroperitoneal Leiomyosarcoma

by Paula González-Alonso, Cristina Chamizo, Víctor Moreno, Juan Madoz-Gúrpide, Nerea Carvajal, Lina Daoud, Sandra Zazo, Ester Martín-Aparicio, Ion Cristóbal, Raúl Rincón, Jesús García-Foncillas and Federico Rojo

Int. J. Mol. Sci. 2015, 16(8), 19447-19457; https://doi.org/10.3390/ijms160819447 - 17 Aug 2015

Cited by 3 | Viewed by 7445

Abstract

Mutations in Human Epidermal Growth Factor Receptors (HER) are associated with poor prognosis of several types of solid tumors. Although HER-mutation detection methods are currently available, such as Next-Generation Sequencing (NGS), alternative pyrosequencing allow the rapid characterization of specific mutations. We developed specific [...] Read more.

Mutations in Human Epidermal Growth Factor Receptors (HER) are associated with poor prognosis of several types of solid tumors. Although HER-mutation detection methods are currently available, such as Next-Generation Sequencing (NGS), alternative pyrosequencing allow the rapid characterization of specific mutations. We developed specific PCR-based pyrosequencing assays for identification of most prevalent HER2 and HER3 mutations, including S310F/Y, R678Q, L755M/P/S/W, V777A/L/M, 774-776 insertion, and V842I mutations in HER2, as well as M91I, V104M/L, D297N/V/Y, and E332E/K mutations in HER3. We tested 85 Formalin Fixed and Paraffin Embbeded (FFPE) samples and we detected three HER2-V842I mutations in colorectal carcinoma (CRC), ovarian carcinoma, and pancreatic carcinoma patients, respectively, and a HER2-L755M mutation in a CRC specimen. We also determined the presence of a HER3-E332K mutation in an urothelial carcinoma sample, and two HER3-D297Y mutations, in both gastric adenocarcinoma and CRC specimens. The D297Y mutation was previously detected in breast and gastric tumors, but not in CRC. Moreover, we found a not-previously-described HER3-E332E synonymous mutation in a retroperitoneal leiomyosarcoma patient. The pyrosequencing assays presented here allow the detection and characterization of specific HER2 and HER3 mutations. These pyrosequencing assays might be implemented in routine diagnosis for molecular characterization of HER2/HER3 receptors as an alternative to complex NGS approaches. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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18 pages, 1674 KiB

Open AccessArticle

UV Differentially Induces Oxidative Stress, DNA Damage and Apoptosis in BCR-ABL1-Positive Cells Sensitive and Resistant to Imatinib

by Ewelina Synowiec, Grazyna Hoser, Katarzyna Wojcik, Elzbieta Pawlowska, Tomasz Skorski and Janusz Błasiak

Int. J. Mol. Sci. 2015, 16(8), 18111-18128; https://doi.org/10.3390/ijms160818111 - 5 Aug 2015

Cited by 16 | Viewed by 6514

Abstract

Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, [...] Read more.

Chronic myeloid leukemia (CML) cells express the active BCR-ABL1 protein, which has been targeted by imatinib in CML therapy, but resistance to this drug is an emerging problem. BCR-ABL1 induces endogenous oxidative stress promoting genomic instability and imatinib resistance. In the present work, we investigated the extent of oxidative stress, DNA damage, apoptosis and expression of apoptosis-related genes in BCR-ABL1 cells sensitive and resistant to imatinib. The resistance resulted either from the Y253H mutation in the BCR-ABL1 gene or incubation in increasing concentrations of imatinib (AR). UV irradiation at a dose rate of 0.12 J/(m²·s) induced more DNA damage detected by the T4 pyrimidine dimers glycosylase and hOGG1, recognizing oxidative modifications to DNA bases in imatinib-resistant than -sensitive cells. The resistant cells displayed also higher susceptibility to UV-induced apoptosis. These cells had lower native mitochondrial membrane potential than imatinib-sensitive cells, but UV-irradiation reversed that relationship. We observed a significant lowering of the expression of the succinate dehydrogenase (SDHB) gene, encoding a component of the complex II of the mitochondrial respiratory chain, which is involved in apoptosis sensing. Although detailed mechanism of imatinib resistance in AR cells in unknown, we detected the presence of the Y253H mutation in a fraction of these cells. In conclusion, imatinib-resistant cells may display a different extent of genome instability than their imatinib-sensitive counterparts, which may follow their different reactions to both endogenous and exogenous DNA-damaging factors, including DNA repair and apoptosis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 3202 KiB

Open AccessArticle

Dysregulation of PAK1 Is Associated with DNA Damage and Is of Prognostic Importance in Primary Esophageal Small Cell Carcinoma

by Jinfeng Gan, Yuling Zhang, Xiurong Ke, Chong Tan, Hongzheng Ren, Hongmei Dong, Jiali Jiang, Shaobin Chen, Yixuan Zhuang and Hao Zhang

Int. J. Mol. Sci. 2015, 16(6), 12035-12050; https://doi.org/10.3390/ijms160612035 - 27 May 2015

Cited by 18 | Viewed by 5863

Abstract

Primary esophageal small cell carcinoma (PESCC) is a rare, but fatal subtype of esophageal carcinoma. No effective therapeutic regimen for it. P21-activated kinase 1 (PAK1) is known to function as an integrator and an indispensable node of major growth factor signaling and the [...] Read more.

Primary esophageal small cell carcinoma (PESCC) is a rare, but fatal subtype of esophageal carcinoma. No effective therapeutic regimen for it. P21-activated kinase 1 (PAK1) is known to function as an integrator and an indispensable node of major growth factor signaling and the molecular therapy targeting PAK1 has been clinical in pipeline. We thus set to examine the expression and clinical impact of PAK1 in PESCC. The expression of PAK1 was detected in a semi-quantitative manner by performing immunohistochemistry. PAK1 was overexpressed in 22 of 34 PESCC tumors, but in only 2 of 18 adjacent non-cancerous tissues. Overexpression of PAK1 was significantly associated with tumor location (p = 0.011), lymph node metastasis (p = 0.026) and patient survival (p = 0.032). We also investigated the association of PAK1 with DNA damage, a driven cause for malignancy progression. γH2AX, a DNA damage marker, was detectable in 18 of 24 (75.0%) cases, and PAK1 expression was associated with γH2AX (p = 0.027). Together, PAK1 is important in metastasis and progression of PESCC. The contribution of PAK1 to clinical outcomes may be involved in its regulating DNA damage pathway. Further studies are worth determining the potentials of PAK1 as prognostic indicator and therapeutic target for PESCC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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17 pages, 4560 KiB

Open AccessArticle

Exposure of Tumor-Associated Macrophages to Apoptotic MCF-7 Cells Promotes Breast Cancer Growth and Metastasis

by Na Zhou, Yizhuang Zhang, Xuehui Zhang, Zhen Lei, Ruobi Hu, Hui Li, Yiqing Mao, Xi Wang, David M. Irwin, Gang Niu and Huanran Tan

Int. J. Mol. Sci. 2015, 16(6), 11966-11982; https://doi.org/10.3390/ijms160611966 - 26 May 2015

Cited by 39 | Viewed by 8432 | Correction

Abstract

Tumor-associated macrophages (TAMs) have been found to be associated with the progression and metastasis of breast cancer. To clarify the mechanisms underlying the crosstalk between TAMs and cancer stem cells (CSCs) in breast cancer recurrence and metastasis, we used a co-culture model of [...] Read more.

Tumor-associated macrophages (TAMs) have been found to be associated with the progression and metastasis of breast cancer. To clarify the mechanisms underlying the crosstalk between TAMs and cancer stem cells (CSCs) in breast cancer recurrence and metastasis, we used a co-culture model of macrophages and apoptotic human breast cancer cell line MCF-7 cells to investigate the effects of TAMs on MCF-7 in vitro and in vivo. Macrophages co-cultured with apoptotic MCF-7 had increased tumor growth and metastatic ability in a nude mouse transplantation assay. The macrophages exposed to apoptotic cells also induce an increase in the proportion of CD44⁺/CD24⁻ cancer stem-like cells, as well as their proliferative ability accompanied with an increase in mucin1 (MUC1) expression. During this process, macrophages secreted increased amounts of interleukin 6 (IL-6) leading to increased phosphorylation of signal transducers and activators of transcription 3 (STAT3), which likely explains the increased transcription of STAT3 target genes such as TGF-β1 and HIF-1α. Our results indicate that when cancer cells endure chemotherapy induced apoptosis, macrophages in their microenvironment can then activate cancer stem cells to promote cancer growth and metastasis by secreting IL-6, which activates STAT3 phosphorylation to regulate the transcription of its downstream target genes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 3912 KiB

Open AccessArticle

VEGFR-1 Overexpression Identifies a Small Subgroup of Aggressive Prostate Cancers in Patients Treated by Prostatectomy

by Maria Christina Tsourlakis, Puya Khosrawi, Philipp Weigand, Martina Kluth, Claudia Hube-Magg, Sarah Minner, Christina Koop, Markus Graefen, Hans Heinzer, Corinna Wittmer, Guido Sauter, Till Krech, Waldemar Wilczak, Hartwig Huland, Ronald Simon, Thorsten Schlomm and Stefan Steurer

Int. J. Mol. Sci. 2015, 16(4), 8591-8606; https://doi.org/10.3390/ijms16048591 - 16 Apr 2015

Cited by 6 | Viewed by 7053

Abstract

The VEGFR-1 is suggested to promote tumor progression. In the current study we analyzed prevalence and prognostic impact of the VEGFR-1 by immunohistochemistry on a tissue microarray containing more than 3000 prostate cancer specimens. Results were compared to tumor phenotype, ETS-related gene (ERG) [...] Read more.

The VEGFR-1 is suggested to promote tumor progression. In the current study we analyzed prevalence and prognostic impact of the VEGFR-1 by immunohistochemistry on a tissue microarray containing more than 3000 prostate cancer specimens. Results were compared to tumor phenotype, ETS-related gene (ERG) status, and biochemical recurrence. Membranous VEGFR-1 expression was detectable in 32.6% of 2669 interpretable cancers and considered strong in 1.7%, moderate in 6.7% and weak in 24.2% of cases. Strong VEGFR-1 expression was associated with TMPRSS2:ERG fusion status as determined by fluorescence in situ hybridization (FISH) and immunohistochemistry (p < 0.0001 each). Elevated VEGFR-1 expression was linked to high Gleason grade and advanced pT stage in TMPRSS2:ERG negative cancers (p = 0.0008 and p = 0.001), while these associations were absent in TMPRSS2:ERG positive cancers. VEGFR-1 expression was also linked to phosphatase and tensin homolog (PTEN) deletions. A comparison with prostate specific antigen (PSA) recurrence revealed that the 1.7% of prostate cancers with the highest VEGFR-1 levels had a strikingly unfavorable prognosis. This could be seen in all cancers, in the subsets of TMPRSS2:ERG positive or negative, PTEN deleted or undeleted carcinomas (p < 0.0001 each). High level VEGFR-1 expression is infrequent in prostate cancer, but identifies a subgroup of aggressive cancers, which may be candidates for anti-VEGFR-1 targeted therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 1962 KiB

Open AccessArticle

Psoralea glandulosa as a Potential Source of Anticancer Agents for Melanoma Treatment

by Alejandro Madrid, Venera Cardile, César González, Ivan Montenegro, Joan Villena, Silvia Caggia, Adriana Graziano and Alessandra Russo

Int. J. Mol. Sci. 2015, 16(4), 7944-7959; https://doi.org/10.3390/ijms16047944 - 9 Apr 2015

Cited by 23 | Viewed by 7196

Abstract

With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1 [...] Read more.

With the aim of identifying novel agents with antigrowth and pro-apoptotic activity on melanoma cancer, the present study was undertaken to investigate the biological activity of the resinous exudate of aerial parts from Psoralea glandulosa, and its active components (bakuchiol (1), 3-hydroxy-bakuchiol (2) and 12-hydroxy-iso-bakuchiol (3)) against melanoma cells (A2058). In addition, the effect in cancer cells of bakuchiol acetate (4), a semi-synthetic derivative of bakuchiol, was examined. The results obtained show that the resinous exudate inhibited the growth of cancer cells with IC₅₀ value of 10.5 μg/mL after 48 h of treatment, while, for pure compounds, the most active was the semi-synthetic compound 4. Our data also demonstrate that resin is able to induce apoptotic cell death, which could be related to an overall action of the meroterpenes present. In addition, our data seem to indicate that the apoptosis correlated to the tested products appears, at least in part, to be associated with an increase of reactive oxygen species (ROS) production. In summary, our study provides the first evidence that P. glandulosa may be considered a source of useful molecules in the development of analogues with more potent efficacy against melanoma cells. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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17 pages, 3645 KiB

Open AccessArticle

In Utero Exposure to Low-Dose Alcohol Induces Reprogramming of Mammary Development and Tumor Risk in MMTV-erbB-2 Transgenic Mice

by Zhikun Ma, Amanda J. Blackwelder, Harry Lee, Ming Zhao and Xiaohe Yang

Int. J. Mol. Sci. 2015, 16(4), 7655-7671; https://doi.org/10.3390/ijms16047655 - 7 Apr 2015

Cited by 5 | Viewed by 5985

Abstract

There is increasing evidence that prenatal exposure to environmental factors may modify breast cancer risk later in life. This study aimed to investigate the effects of in utero exposure to low-dose alcohol on mammary development and tumor risk. Pregnant MMTV-erbB-2 mice were exposed [...] Read more.

There is increasing evidence that prenatal exposure to environmental factors may modify breast cancer risk later in life. This study aimed to investigate the effects of in utero exposure to low-dose alcohol on mammary development and tumor risk. Pregnant MMTV-erbB-2 mice were exposed to alcohol (6 g/kg/day) between day 13 and day 19 of gestation, and the female offspring were examined for tumor risk. Whole mount analysis indicated that in utero exposure to low-dose alcohol induced significant increases in ductal extension at 10 weeks of age. Molecular analysis showed that in utero alcohol exposure induced upregulation of ERα signaling and activation of Akt and Erk1/2 in pubertal mammary glands. However, enhanced signaling in the EGFR/erbB-2 pathway appeared to be more prominent in 10-week-old glands than did signaling in the other pathways. Interestingly, tumor development in mice with in utero exposure to low-dose alcohol was slightly delayed compared to control mice, but tumor multiplicity was increased. The results indicate that in utero exposure to low-dose alcohol induces the reprogramming of mammary development by mechanisms that include altered signaling in the estrogen receptor (ER) and erbB-2 pathways. The intriguing tumor development pattern might be related to alcohol dose and exposure conditions, and warrants further investigation. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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12 pages, 1729 KiB

Open AccessArticle

Tetraspanin 8-Rictor-Integrin α3 Complex Is Required for Glioma Cell Migration

by Si-Jian Pan, Shi-Kun Zhan, Yi-Xin Pan, Wei Liu, Liu-Guan Bian, Bomin Sun and Qing-Fang Sun

Int. J. Mol. Sci. 2015, 16(3), 5363-5374; https://doi.org/10.3390/ijms16035363 - 9 Mar 2015

Cited by 36 | Viewed by 6493

Abstract

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in [...] Read more.

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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14 pages, 1287 KiB

Open AccessArticle

Exploring Prostate Cancer Genome Reveals Simultaneous Losses of PTEN, FAS and PAPSS2 in Patients with PSA Recurrence after Radical Prostatectomy

by Chinyere Ibeawuchi, Hartmut Schmidt, Reinhard Voss, Ulf Titze, Mahmoud Abbas, Joerg Neumann, Elke Eltze, Agnes Marije Hoogland, Guido Jenster, Burkhard Brandt and Axel Semjonow

Int. J. Mol. Sci. 2015, 16(2), 3856-3869; https://doi.org/10.3390/ijms16023856 - 11 Feb 2015

Cited by 17 | Viewed by 9299

Abstract

The multifocal nature of prostate cancer (PCa) creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological [...] Read more.

The multifocal nature of prostate cancer (PCa) creates a challenge to patients’ outcome prediction and their clinical management. An approach that scrutinizes every cancer focus is needed in order to generate a comprehensive evaluation of the disease, and by correlating to patients’ clinico-pathological information, specific prognostic biomarker can be identified. Our study utilized the Affymetrix SNP 6.0 Genome-wide assay to investigate forty-three fresh frozen PCa tissue foci from twenty-three patients. With a long clinical follow-up period that ranged from 2.0–9.7 (mean 5.4) years, copy number variation (CNV) data was evaluated for association with patients’ PSA status during follow-up. From our results, the loss of unique genes on 10q23.31 and 10q23.2–10q23.31 were identified to be significantly associated to PSA recurrence (p < 0.05). The implication of PTEN and FAS loss (10q23.31) support previous reports due to their critical roles in prostate carcinogenesis. Furthermore, we hypothesize that the PAPSS2 gene (10q23.2–10q23.31) may be functionally relevant in post-operative PSA recurrence because of its reported role in androgen biosynthesis. It is suggestive that the loss of the susceptible region on chromosome 10q, which implicates PTEN, FAS and PAPSS2 may serve as genetic predictors of PSA recurrence after radical prostatectomy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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14 pages, 1480 KiB

Open AccessArticle

Expression and Significance of CD44, CD47 and c-met in Ovarian Clear Cell Carcinoma

by Huimin Wang, Mingzi Tan, Song Zhang, Xiao Li, Jian Gao, Danye Zhang, Yingying Hao, Song Gao, Juanjuan Liu and Bei Lin

Int. J. Mol. Sci. 2015, 16(2), 3391-3404; https://doi.org/10.3390/ijms16023391 - 4 Feb 2015

Cited by 69 | Viewed by 8018

Abstract

Aims: The aim of the present study is to investigate the differential expression of CD44, CD47 and c-met in ovarian clear cell carcinoma (OCCC), the correlation in their expression and their relationship with the biological behavior of OCCC. Methods: We used immunohistochemistry to [...] Read more.

Aims: The aim of the present study is to investigate the differential expression of CD44, CD47 and c-met in ovarian clear cell carcinoma (OCCC), the correlation in their expression and their relationship with the biological behavior of OCCC. Methods: We used immunohistochemistry to examine the expression of CD44, CD47 and c-met in OCCC (86 cases) and investigated the effects of the expression and interaction of these molecules on the development of OCCC. Results: CD44, CD47 and c-met expression was significantly high in OCCC. Expression of CD44 and CD47 correlated with patient surgical stage, chemotherapy resistance and prognosis (all p < 0.05), and expression of c-met correlated with chemotherapy resistance and prognosis (all p < 0.05), but did not correlate with lymph node metastasis (all p > 0.05). The surgical stage, CD44, CD47 and c-met expression were independent risk factors for OCCC prognosis (all p < 0.05). Patients with low levels of CD44, CD47 and c-met showed better survival than those with high levels (all p < 0.05). There was a positive correlation between CD44 (or CD47) and c-met, as well as between CD44 and CD47 (the Spearman correlation coefficient r_swas 0.783, 0.776 and 0.835, respectively, all p < 0.01). Additionally, pairwise correlation analysis of these three markers shows that the high expression of CD44/CD47, CD44/c-met and CD47/c-met were correlated with patient surgical stage, chemotherapy resistance and prognosis (all p < 0.05), but did not correlate with lymph node metastasis (all p > 0.05). Conclusions: Expression of CD44, CD47 and c-met was upregulated in OCCC and pairwise correlation. CD44, CD47 and c-met may have synergistic effects on the development of OCCC and are prognostic factors for ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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13 pages, 2427 KiB

Open AccessArticle

FBXW7 Acts as an Independent Prognostic Marker and Inhibits Tumor Growth in Human Osteosarcoma

by Zhanchun Li, Jie Xiao, Kongzu Hu, Gang Wang, Maoqiang Li, Jidong Zhang and Guangqi Cheng

Int. J. Mol. Sci. 2015, 16(2), 2294-2306; https://doi.org/10.3390/ijms16022294 - 22 Jan 2015

Cited by 23 | Viewed by 7038

Abstract

F-box and WD repeat domain-containing 7 (FBXW7) is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS) cases [...] Read more.

F-box and WD repeat domain-containing 7 (FBXW7) is a potent tumor suppressor in human cancers including breast cancer, colorectal cancer, gastric cancer and hepatocellular carcinoma. In this study, we found that the expressions of FBXW7 protein and mRNA levels in osteosarcoma (OS) cases were significantly lower than those in normal bone tissues. Clinical analysis indicated that FBXW7 was expressed at lower levels in OS patients with advanced clinical stage, high T classification and poor histological differentiation. Furthermore, we demonstrated that high expression of FBXW7 was correlated with a better 5-year survival of OS patients. Multivariate Cox regression analysis indicated that FBXW7 was an independent prognostic marker in OS. Our in vitro studies showed that FBXW7 overexpression inhibited cell cycle transition and cell proliferation, and promoted apoptosis in both U2OS and MG-63 cells. In a nude mouse xenograft model, FBXW7 overexpression slowed down tumor growth by inducing apoptosis and growth arrest. Mechanistically, FBXW7 inversely regulated oncoprotein c-Myc and cyclin E levels in both U2OS and MG-63 cells. Together these findings suggest that FBXW7 may serve as a prognostic biomarker and inhibit tumor progression by inducing apoptosis and growth arrest in OS. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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13 pages, 2334 KiB

Open AccessArticle

Connexin 43 Suppresses Tumor Angiogenesis by Down-Regulation of Vascular Endothelial Growth Factor via Hypoxic-Induced Factor-1α

by Wei-Kuang Wang, Man-Chin Chen, Hon-Fai Leong, Yu-Liang Kuo, Chun-Yu Kuo and Che-Hsin Lee

Int. J. Mol. Sci. 2015, 16(1), 439-451; https://doi.org/10.3390/ijms16010439 - 26 Dec 2014

Cited by 52 | Viewed by 7629

Abstract

Previous work showed that connexin 43 (Cx43) reduced the expression of hypoxic-induced factor-1α (HIF-1α) in astrocytes. HIF-1α is a master transcription factor for angiogenesis in tumor. Angiogenesis is essential for tumor progression. Here, we investigated the role of Cx43 in vascular endothelial growth [...] Read more.

Previous work showed that connexin 43 (Cx43) reduced the expression of hypoxic-induced factor-1α (HIF-1α) in astrocytes. HIF-1α is a master transcription factor for angiogenesis in tumor. Angiogenesis is essential for tumor progression. Here, we investigated the role of Cx43 in vascular endothelial growth factor (VEGF) production and angiogenesis in murine tumor. In the study, mouse B16F10 and 4T1 cells were overexpressed or knockdown with Cx43. The expression profiles as well as activity of the treated cells were examined. Furthermore, reduced Cx43 expression in B16F10 and 4T1 cells causes increased expression of VEGF and enhanced the proliferation of endothelial cells. On the contrary, the expression of VEGF and the proliferation of endothelial were increased in the conditioned medium of Cx43-knockdown tumor cells. We subcutaneously transplanted Cx43-overexpressing B16F10 cells into mice to evaluate the roles of Cx43 in the tumor angiogenesis. Both tumor size and the number of vessels growing in the tumor were markedly decreased compare with control group. Our findings suggest that Cx43 inhibited tumor growth by reducing angiogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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15 pages, 10295 KiB

Open AccessArticle

High Levels of KAP1 Expression Are Associated with Aggressive Clinical Features in Ovarian Cancer

by Yanfen Cui, Shaobin Yang, Xin Fu, Jingwen Feng, Shilei Xu and Guoguang Ying

Int. J. Mol. Sci. 2015, 16(1), 363-377; https://doi.org/10.3390/ijms16010363 - 26 Dec 2014

Cited by 48 | Viewed by 7680

Abstract

KAP1 is an universal corepressor for Kruppel-associated box zinc finger proteins in both normal and tumor cells. In this study, the biological function and clinical significance of KAP1 expression in ovarian cancer were investigated. Immunohistological staining of KAP1 was evaluated in 111 patients [...] Read more.

KAP1 is an universal corepressor for Kruppel-associated box zinc finger proteins in both normal and tumor cells. In this study, the biological function and clinical significance of KAP1 expression in ovarian cancer were investigated. Immunohistological staining of KAP1 was evaluated in 111 patients with ovarian epithelial cancer, 15 with ovarian borderline tumor, and 20 normal ovarian tissue. The correlations of KAP1 expression with clinicopathological features were studied. Kaplan-Meier analysis and Cox proportional hazard modeling were used to assess overall survival to analyze the effect of KAP1 expression on the prognosis of ovarian cancer. The positive rates of KAP1 were significantly higher in ovarian epithelial cancer (55.7%) and borderline tumor (20.0%) than in normal ovarian tissue (5.0%) (all p < 0.01). KAP1 expression correlated significantly with clinical stage (χ² = 14.57, p < 0.0001), pathological grade (χ² = 6.06, p = 0.048) and metastases (χ² =10.38, p = 0.001). Patients with high KAP 1 levels showed poor survival (p < 0.0001). Multivariate analysis showed that KAP1 high expression was an independent predictor for ovarian cancer patients (hazard ratio = 0.463; 95% confidence interval = 0.230–0.9318, p = 0.031). Functionally, depletion of KAP1 by siRNA inhibited ovarian cancer cell proliferation, cell migration. KAP1 expression correlated with aggressive clinical features in ovarian cancer. High KAP1 expression was a prognostic factor of ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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10 pages, 1018 KiB

Open AccessArticle

Twist-1 Up-Regulation in Carcinoma Correlates to Poor Survival

by Alimujiang Wushou, Jing Hou, Ya-Jun Zhao and Zhi-Ming Shao

Int. J. Mol. Sci. 2014, 15(12), 21621-21630; https://doi.org/10.3390/ijms151221621 - 25 Nov 2014

Cited by 68 | Viewed by 8032

Abstract

Epithelial-to-mesenchymal transition (EMT) facilitates tumor metastasis. Twist is a basic helix-loop-helix protein that modulates many target genes through E-box-responsive elements. There are two twist-like proteins, Twist-1 and Twist-2, sharing high structural homology in mammals. Twist-1 was found to [...] Read more.

Epithelial-to-mesenchymal transition (EMT) facilitates tumor metastasis. Twist is a basic helix-loop-helix protein that modulates many target genes through E-box-responsive elements. There are two twist-like proteins, Twist-1 and Twist-2, sharing high structural homology in mammals. Twist-1 was found to be a key factor in the promotion of metastasis of cancer cells, and is known to induce EMT. Twist-1 participation in carcinoma progression and metastasis has been reported in a variety of tumors. However, controversy exists concerning the correlation between Twist-1 and prognostic value with respect to carcinoma. A systematic review and meta-analysis were performed to determine whether the expression of Twist-1 was associated with the prognosis of carcinoma patients. This analysis included 17 studies: four studies evaluated lung cancer, three evaluated head and neck cancer, two evaluated breast cancer, two evaluated esophageal cancer, two evaluated liver cancer and one each evaluated osteosarcoma, bladder, cervical and ovarian cancer. A total of 2006 patients were enrolled in these studies, and the median trial sample size was 118 patients. Twist-1 expression was associated with worse overall survival (OS) at both 3 years (hazard ratio “HR” for death = 2.13, 95% CI = 1.86 to 2.45, p < 0.001) and 5 years (HR for death = 2.01, 95% CI = 1.76 to 2.29, p < 0.001). Expression of Twist-1 is associated with worse survival in carcinoma. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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15 pages, 6877 KiB

Open AccessArticle

Growth Suppression of Colorectal Cancer by Plant-Derived Multiple mAb CO17-1A × BR55 via Inhibition of ERK1/2 Phosphorylation

by Dong Hoon Kwak, Ghislain Moussavou, Ju Hyoung Lee, Sung Youn Heo, Kisung Ko, Kyung-A Hwang, Seung-Joo Jekal and Young-Kug Choo

Int. J. Mol. Sci. 2014, 15(11), 21105-21119; https://doi.org/10.3390/ijms151121105 - 14 Nov 2014

Cited by 1 | Viewed by 7153

Abstract

We have generated the transgenic Tabaco plants expressing multiple monoclonal antibody (mAb) CO7-1A × BR55 by cross-pollinating with mAb CO17-1A and mAb BR55. We have demonstrated the anti-cancer effect of plant-derived multiple mAb CO17-1A × BR55. We find that co-treatment of colorectal mAbs [...] Read more.

We have generated the transgenic Tabaco plants expressing multiple monoclonal antibody (mAb) CO7-1A × BR55 by cross-pollinating with mAb CO17-1A and mAb BR55. We have demonstrated the anti-cancer effect of plant-derived multiple mAb CO17-1A × BR55. We find that co-treatment of colorectal mAbs (anti-epithelial cellular adhesion molecule (EpCAM), plant-derived monoclonal antibody (mAb^P) CO17-1A and mAb^P CO17-1A × BR55) with RAW264.7 cells significantly inhibited the cell growth in SW620 cancer cells. In particular, multi mAb^P CO17-1A × BR55 significantly and efficiently suppressed the growth of SW620 cancer cells compared to another mAbs. Apoptotic death-positive cells were significantly increased in the mAb^P CO17-1A × BR55-treated. The mAb^P CO17-1A × BR55 treatment significantly decreased the expression of B-Cell lymphoma-2 (BCl-2), but the expression of Bcl-2-associated X protein (Bax), and cleaved caspase-3 were markedly increased. In vivo, the mAb^P CO17-1A × BR55 significantly and efficiently inhibited the growth of colon tumors compared to another mAbs. The apoptotic cell death and inhibition of pro-apoptotic proteins expression were highest by treatment with mAb^P CO17-1A × BR55. In addition, the mAb^P CO17-1A × BR55 significantly inhibited the extracellular signal-regulated kinase 1 and 2 (ERK1/2) phosphorylation in cancer cells and tumors. Therefore, this study results suggest that multiple mAb^P CO17-1A × BR55 has a significant effect on apoptosis-mediated anticancer by suppression of ERK1/2 phosphorylation in colon cancer compared to another mAbs. In light of these results, further clinical investigation should be conducted on mAb^P CO17-1A × BR55 to determine its possible chemopreventive and/or therapeutic efficacy against human colon cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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14 pages, 4460 KiB

Open AccessArticle

MicroRNA-130b Promotes Cell Aggressiveness by Inhibiting Peroxisome Proliferator-Activated Receptor Gamma in Human Hepatocellular Carcinoma

by Kangsheng Tu, Xin Zheng, Changwei Dou, Chao Li, Wei Yang, Yingmin Yao and Qingguang Liu

Int. J. Mol. Sci. 2014, 15(11), 20486-20499; https://doi.org/10.3390/ijms151120486 - 7 Nov 2014

Cited by 69 | Viewed by 8586

Abstract

MircroRNA-130b (miR-130b) is proposed as a novel tumor-related miRNA and has been found to be significantly dysregulated in tumors. In this study, the expression level of miR-130b was found to be obviously higher in hepatocellular carcinoma (HCC) tissues than that in nontumor tissues. [...] Read more.

MircroRNA-130b (miR-130b) is proposed as a novel tumor-related miRNA and has been found to be significantly dysregulated in tumors. In this study, the expression level of miR-130b was found to be obviously higher in hepatocellular carcinoma (HCC) tissues than that in nontumor tissues. Further, miR-130b was expressed at significantly higher levels in aggressive and recurrent tumor tissues. Clinical analysis indicated that high-expression of miR-130b was prominently correlated with venous infiltration, high Edmondson-Steiner grading and advanced tumor-node-metastasis (TNM) tumor stage in HCC. Elevated miR-130b expression was observed in all HCC cell lines (HepG2, SMMC-7721, Huh7, Hep3B and MHCC97H) as compared with that in a nontransformed hepatic cell line (LO2). Furthermore, an inverse correlation between miR-130b and E-cadherin and a positive correlation between miR-130b and Vimentin were observed in HCC tissues. Down-regulation of miR-130b expression reduced invasion and migration in both Hep3B and MHCC97H cells. Peroxisome proliferator-activated receptor gamma (PPAR-γ) was inversely correlated with miR-130b expression in HCC tissues. In addition, down-regulation of miR-130b restored PPAR-γ expression and subsequently suppressed epithelial-mesenchymal transition (EMT) in HCC cells. We identified PPARγ as a direct target of miR-130b in HCC in vitro. Notably, PPAR-γ knockdown abolished down-regulation of miR-130b-inhibited EMT in MHCC97H cells. In conclusion, miR-130b may promote HCC cell migration and invasion by inhibiting PPAR-γ and subsequently inducing EMT. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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18 pages, 6783 KiB

Open AccessArticle

Validation of Bmi1 as a Therapeutic Target of Hepatocellular Carcinoma in Mice

by Shibo Qi, Bin Li, Tan Yang, Yong Liu, Shanshan Cao, Xingxing He, Peng Zhang, Lei Li and Chuanrui Xu

Int. J. Mol. Sci. 2014, 15(11), 20004-20021; https://doi.org/10.3390/ijms151120004 - 3 Nov 2014

Cited by 10 | Viewed by 7554

Abstract

Bmi1 is a member of the polycomb group family of proteins, and it drives the carcinogenesis of various cancers and governs the self-renewal of multiple types of stem cells. Our previous studies have revealed that Bmi1 acts as an oncogene in hepatic carcinogenesis [...] Read more.

Bmi1 is a member of the polycomb group family of proteins, and it drives the carcinogenesis of various cancers and governs the self-renewal of multiple types of stem cells. Our previous studies have revealed that Bmi1 acts as an oncogene in hepatic carcinogenesis in an INK4a/ARF locus independent manner. However, whether Bmi1 can be used as a potential target for hepatocellular carcinoma treatment has not been fully confirmed yet. Here, we show that perturbation of Bmi1 expression by using short hairpin RNA can inhibit the tumorigenicity and tumor growth of hepatocellular carcinoma cells both in vitro and in vivo. Importantly, Bmi1 knockdown can block the tumor growth, both in the initiating stages and the fast growing stages. Cellular biology analysis revealed that Bmi1 knockdown induces cell cycle arrest and apoptosis. Our findings verify Bmi1 as a qualified treatment target for hepatocellular carcinoma (HCC) and support Bmi1 targeting treatment with chemotherapeutic agents. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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16 pages, 3051 KiB

Open AccessArticle

Evaluating the Role of PTH in Promotion of Chondrosarcoma Cell Proliferation and Invasion by Inhibiting Primary Cilia Expression

by Wei Xiang, Ting Jiang, Fengjing Guo, Tao Xu, Chen Gong, Peng Cheng, Libo Zhao, Weiting Cheng and Kai Xu

Int. J. Mol. Sci. 2014, 15(11), 19816-19831; https://doi.org/10.3390/ijms151119816 - 31 Oct 2014

Cited by 12 | Viewed by 6647

Abstract

Chondrosarcoma is characterized by secretion of a cartilage-like matrix, with high proliferation ability and metastatic potential. Previous studies have shown that parathyroid hormone-related protein (PTHrP) has a close relationship with various tumor types. The objectives of this study were to research the function [...] Read more.

Chondrosarcoma is characterized by secretion of a cartilage-like matrix, with high proliferation ability and metastatic potential. Previous studies have shown that parathyroid hormone-related protein (PTHrP) has a close relationship with various tumor types. The objectives of this study were to research the function played by PTHrP in human chondrosarcoma, especially targeting cell proliferation and invasion, and to search for the potential interaction between PTHrP and primary cilia in tumorigenesis. Surgical resection tissues and the human chondrosarcoma cell line SW1353 were used in the scientific research. Cells were stimulated with an optimum concentration of recombinant PTH (1-84), and siRNA was used to interfere with internal PTHrP. Cell proliferation and invasion assays were applied, including MTS-8 cell proliferation assay, Western blot, RT-PCR, Transwell invasion assay, and immunohistochemistry and immunofluorescence assays. A high level of PTHrP expression was found in human chondrosarcoma tissues, and recombinant PTH exhibited positive promotion in tumor cell proliferation and invasion. In the meantime, PTHrP could inhibit the assembly of primary cilia and regulate downstream gene expression. These findings indicate that PTHrP can regulate tumor cell proliferation and invasion ability, possibly through suppression of primary cilia assembly. Thus, restricting PTHrP over-expression is a feasible potential therapeutic method for chondrosarcoma. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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18 pages, 885 KiB

Open AccessArticle

Active Transport Can Greatly Enhance Cdc20:Mad2 Formation

by Bashar Ibrahim and Richard Henze

Int. J. Mol. Sci. 2014, 15(10), 19074-19091; https://doi.org/10.3390/ijms151019074 - 21 Oct 2014

Cited by 12 | Viewed by 7325

Abstract

To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis. The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint [...] Read more.

To guarantee genomic integrity and viability, the cell must ensure proper distribution of the replicated chromosomes among the two daughter cells in mitosis. The mitotic spindle assembly checkpoint (SAC) is a central regulatory mechanism to achieve this goal. A dysfunction of this checkpoint may lead to aneuploidy and likely contributes to the development of cancer. Kinetochores of unattached or misaligned chromosomes are thought to generate a diffusible “wait-anaphase” signal, which is the basis for downstream events to inhibit the anaphase promoting complex/cyclosome (APC/C). The rate of Cdc20:C-Mad2 complex formation at the kinetochore is a key regulatory factor in the context of APC/C inhibition. Computer simulations of a quantitative SAC model show that the formation of Cdc20:C-Mad2 is too slow for checkpoint maintenance when cytosolic O-Mad2 has to encounter kinetochores by diffusion alone. Here, we show that an active transport of O-Mad2 towards the spindle mid-zone increases the efficiency of Mad2-activation. Our in-silico data indicate that this mechanism can greatly enhance the formation of Cdc20:Mad2 and furthermore gives an explanation on how the “wait-anaphase” signal can dissolve abruptly within a short time. Our results help to understand parts of the SAC mechanism that remain unclear. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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14 pages, 2022 KiB

Open AccessArticle

TPX2 Is a Prognostic Marker and Contributes to Growth and Metastasis of Human Hepatocellular Carcinoma

by Yuqi Huang, Wenbin Guo and Heping Kan

Int. J. Mol. Sci. 2014, 15(10), 18148-18161; https://doi.org/10.3390/ijms151018148 - 9 Oct 2014

Cited by 49 | Viewed by 7645

Abstract

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that [...] Read more.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2), a microtubule-associated protein, impacts spindle assembly in human cells. Several studies have demonstrated that TPX2 is overexpressed in different types of human cancers and promotes tumor growth and metastasis. In this study, we found that the expression level of TPX2 was obviously higher in hepatocellular carcinoma (HCC) tissues than in matched nontumor tissues. Elevated expressions of TPX2 mRNA were observed in all HCC cell lines (HepG2, Hep3B, SMMC-7721, Bel-7402 and Huh7) as compared with that in a non-transformed hepatic cell line (LO2). Clinical analysis indicated that the positive expression of TPX2 was significantly correlated with venous infiltration, high Edmondson-Steiner grading and advanced TNM tumor stage in HCC. Furthermore, TPX2 was a novel prognostic marker for predicting 5-year overall survival (OS) and disease-free survival (DFS) of HCC patients. In vitro studies found that TPX2 knockdown significantly inhibited cell proliferation and viability in both Hep3B and HepG2 cells. Moreover, TPX2 knockdown obviously slowed down tumor growth in a nude mouse xenograft model. Otherwise, TPX2 knockdown prominently suppressed HCC cell invasion and migration. In conclusion, these results indicate that TPX2 may serve as a prognostic marker and promotes tumorigenesis and metastasis of HCC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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22 pages, 5289 KiB

Open AccessArticle

Expression Profiling of Exosomal miRNAs Derived from Human Esophageal Cancer Cells by Solexa High-Throughput Sequencing

by Juan Liao, Ran Liu, Lihong Yin and Yuepu Pu

Int. J. Mol. Sci. 2014, 15(9), 15530-15551; https://doi.org/10.3390/ijms150915530 - 2 Sep 2014

Cited by 73 | Viewed by 10657

Abstract

Cellular genetic materials, such as microRNAs (miRNAs), mRNAs and proteins, are packaged inside exosomes, small membrane vesicles of endocytic origin that are released into the extracellular environment. These cellular genetic materials can be delivered into recipient cells, where they exert their respective biological [...] Read more.

Cellular genetic materials, such as microRNAs (miRNAs), mRNAs and proteins, are packaged inside exosomes, small membrane vesicles of endocytic origin that are released into the extracellular environment. These cellular genetic materials can be delivered into recipient cells, where they exert their respective biological effects. However, the miRNA profiles and biological functions of exosomes secreted by cancer cells remain unknown. The present study explored the miRNA expression profile and distribution characteristics of exosomes derived from human esophageal cancer cells through Solexa high-throughput sequencing. Results showed that 56,421 (2.94%) unique sequences in cells and 7727 (0.63%) in exosomes matched known miRNAs. A total of 342 and 48 known miRNAs were identified in cells and exosomes, respectively. Moreover, 64 and 32 novel miRNAs were predicted in cells and exosomes, respectively. Significant differences in miRNA expression profiles were found between human esophageal cancer cells and exosomes. These findings provided new insights into the characteristics of miRNAs in exosomes derived from human esophageal cancer cells and the specific roles of miRNAs in intercellular communication mediated by exosomes in esophageal cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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15 pages, 3625 KiB

Open AccessArticle

MRC2 Expression Correlates with TGFβ1 and Survival in Hepatocellular Carcinoma

by Xiaohong Gai, Kangsheng Tu, Zhongtang Lu and Xin Zheng

Int. J. Mol. Sci. 2014, 15(9), 15011-15025; https://doi.org/10.3390/ijms150915011 - 26 Aug 2014

Cited by 36 | Viewed by 7674

Abstract

MRC2 (Mannose Receptor C Type 2) is a constitutively recycling endocytic receptor belonging to the mannose receptor family, which has been found to be closely involved with cancer metastasis. This study attempted to determine MRC2 expression on hepatocellular carcinoma (HCC) and its significance [...] Read more.

MRC2 (Mannose Receptor C Type 2) is a constitutively recycling endocytic receptor belonging to the mannose receptor family, which has been found to be closely involved with cancer metastasis. This study attempted to determine MRC2 expression on hepatocellular carcinoma (HCC) and its significance on postsurgical prognosis of HCCs. The expression of both MRC2 and transforming growth factor (TGFβ1) was detected in tumor tissues and adjacent liver tissues from 96 HCCs by immunohistochemistry staining, and it was found that MRC2 expression in HCC tissues was significantly higher than in adjacent liver tissues. HCCs with higher MRC2 expression had worse prognosis after liver resection. Univariate analysis showed that advanced TNM staging of HCC, higher Edmonson-Steiner classification, intrahepatic metastases, portal vein invasion, higher MRC2 and higher TGFβ1 were the poor prognostic factors. Furthermore, multivariate analysis revealed that intrahepatic metastases, higher MRC2 and higher TGFβ1 were the independent prognostic factors. TGFβ1 treatment up-regulated MRC2 expression, cell migration and invasion of Huh7 cells notably. In addition, knockdown of MRC2 repressed the effect of TGFβ1 on cell migration and invasion. These data suggest that MRC2 overexpression predicts poor prognosis of HCCs after liver resection and MRC2 potentially contributed to TGFβ1-driven up-regulation of cell migration and invasion in HCC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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16 pages, 1937 KiB

Open AccessArticle

Up-Regulated FASN Expression Promotes Transcoelomic Metastasis of Ovarian Cancer Cell through Epithelial-Mesenchymal Transition

by Li Jiang, Hong Wang, Jiarui Li, Xuhong Fang, Hong Pan, Xiangliang Yuan and Ping Zhang

Int. J. Mol. Sci. 2014, 15(7), 11539-11554; https://doi.org/10.3390/ijms150711539 - 27 Jun 2014

Cited by 77 | Viewed by 10727

Abstract

Fatty acid synthase (FASN), responsible for the de novo synthesis of fatty acids, has been shown to act as an oncogene in various human cancers. However, the mechanisms by which FASN favors the progression of ovarian carcinoma remain unknown. In this study, we [...] Read more.

Fatty acid synthase (FASN), responsible for the de novo synthesis of fatty acids, has been shown to act as an oncogene in various human cancers. However, the mechanisms by which FASN favors the progression of ovarian carcinoma remain unknown. In this study, we evaluated FASN expression in ovarian cancer and investigated how FASN regulates the aggressiveness of ovarian cancer cells. Our results show that increased FASN is associated with the peritoneal metastasis of ovarian cancers. Over-expression of FASN results in a significant increase of tumor burden in peritoneal dissemination, accompanied by augment in cellular colony formation and metastatic ability. Correspondingly, FASN knockdown using RNA interference in ovarian cancer cells inhibits the migration in vitro and experimental peritoneal dissemination in vivo. Mechanistic studies reveal that FASN promotes Epithelial-mesenchymal Transition (EMT) via a transcriptional regulation of E-cadherin and N-cadherin, which is also confirmed by luciferase promoter activity analysis. Taken together, our work demonstrates that FASN promotes the peritoneal dissemination of ovarian cancer cells, at least in part through the induction of EMT. These findings suggest that FASN plays a critical role in the peritoneal metastasis of ovarian cancer. Targeting de novo lipogenesis may have a therapeutic potential for advanced ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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17 pages, 1616 KiB

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Clinical Impact of Tumor-Infiltrating Inflammatory Cells in Primary Small Cell Esophageal Carcinoma

by Yuling Zhang, Hongzheng Ren, Lu Wang, Zhifeng Ning, Yixuan Zhuang, Jinfeng Gan, Shaobin Chen, David Zhou, Hua Zhu, Dongfeng Tan and Hao Zhang

Int. J. Mol. Sci. 2014, 15(6), 9718-9734; https://doi.org/10.3390/ijms15069718 - 30 May 2014

Cited by 26 | Viewed by 8891

Abstract

Primary small cell esophageal carcinoma is a rare and aggressive type of gastrointestinal cancer with poor prognosis. In the present study, the impact of tumour infiltrating inflammatory cells on clinico-pathological characteristics and the patients’ prognosis were analysed. A total of 36 small cell [...] Read more.

Primary small cell esophageal carcinoma is a rare and aggressive type of gastrointestinal cancer with poor prognosis. In the present study, the impact of tumour infiltrating inflammatory cells on clinico-pathological characteristics and the patients’ prognosis were analysed. A total of 36 small cell esophageal carcinomas, 19 adjacent normal tissues and 16 esophageal squamous cell carcinoma samples were collected. Qualified pathologists examined eosinophils, neutrophils, lymphocytes and macrophages on histochemical slides. The infiltration of eosinophils and macrophages in small cell esophageal carcinoma was significantly increased as compared with tumor adjacent normal tissues, and was significantly less in esophageal squamous cell carcinoma. Macrophage count was significantly associated with (p = 0.015) lymph node—stage in small cell esophageal carcinoma. When we grouped patients into two groups by counts of infiltrated inflammatory cells, Kaplan-Meier analysis revealed that high macrophage infiltration group (p = 0.004) and high eosinophil infiltration group (p = 0.027) had significantly enhanced survival. In addition, multivariate analysis unveiled that eosinophil count (p = 0.002) and chemotherapy (Yes vs. No, p = 0.001) were independent prognostic indicators. Taken together, infiltration of macrophages and eosinophils into the solid tumor appear to be important in the progression of small cell esophageal carcinoma and patients’ prognosis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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15 pages, 2278 KiB

Open AccessArticle

MicroRNA-103 Promotes Colorectal Cancer by Targeting Tumor Suppressor DICER and PTEN

by Li Geng, Bing Sun, Bo Gao, Zheng Wang, Cheng Quan, Feng Wei and Xue-Dong Fang

Int. J. Mol. Sci. 2014, 15(5), 8458-8472; https://doi.org/10.3390/ijms15058458 - 13 May 2014

Cited by 69 | Viewed by 8864

Abstract

MicroRNAs (miRNAs) are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms for miRNAs in colorectal cancer remain largely unknown. Here, we found that miR-103 is up-regulated in colorectal cancer and [...] Read more.

MicroRNAs (miRNAs) are a class of small, noncoding RNAs that act as key regulators in various physiological and pathological processes. However, the regulatory mechanisms for miRNAs in colorectal cancer remain largely unknown. Here, we found that miR-103 is up-regulated in colorectal cancer and its overexpression is closely associated with tumor proliferation and migration. In addition, repressing the expression of miR-103 apparently inhibits colorectal cancer cell proliferation and migration in vitro and HCT-116 xenograft tumor growth in vivo. Subsequent software analysis and dual-luciferase reporter assay identified two tumor suppressor genes DICER and PTEN as direct targets of miR-103, and up-regulation of DICER and PTEN obtained similar results to that occurred in the silencing of miR-103. In addition, restoration of DICER and PTEN can inhibit miR-103-induced colorectal cancer cell proliferation and migration. Our data collectively demonstrate that miR-103 is an oncogene miRNA that promotes colorectal cancer proliferation and migration through down-regulation of the tumor suppressor genes DICER and PTEN. Thus, miR-103 may represent a new potential diagnostic and therapeutic target for colorectal cancer treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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15 pages, 3089 KiB

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SREBP-1 Has a Prognostic Role and Contributes to Invasion and Metastasis in Human Hepatocellular Carcinoma

by Chao Li, Wei Yang, Junli Zhang, Xin Zheng, Yingmin Yao, Kangsheng Tu and Qingguang Liu

Int. J. Mol. Sci. 2014, 15(5), 7124-7138; https://doi.org/10.3390/ijms15057124 - 25 Apr 2014

Cited by 115 | Viewed by 9784

Abstract

Sterol regulatory element-binding protein 1 (SREBP-1) is a well-known nuclear transcription factor involved in lipid synthesis. Recent studies have focused on its functions in tumor cell proliferation and apoptosis, but its role in cell migration and invasion, especially in hepatocellular carcinoma (HCC), is [...] Read more.

Sterol regulatory element-binding protein 1 (SREBP-1) is a well-known nuclear transcription factor involved in lipid synthesis. Recent studies have focused on its functions in tumor cell proliferation and apoptosis, but its role in cell migration and invasion, especially in hepatocellular carcinoma (HCC), is still unclear. In this study, we found that the expression of SREBP-1 in HCC tissues was significantly higher than those in matched tumor-adjacent tissues (p < 0.05). SREBP-1 was expressed at significantly higher levels in patients with large tumor size, high histological grade and advanced tumor-node-metastasis (TNM) stage (p < 0.05). The positive expression of SREBP-1 correlated with a worse 3-year overall and disease-free survival of HCC patients (p < 0.05). Additionally, SREBP-1 was an independent factor for predicting both 3-year overall and disease-free survival of HCC patients (p < 0.05). In vitro studies revealed that downregulation of SREBP-1 inhibited cell proliferation and induced apoptosis in both HepG2 and MHCC97L cells (p < 0.05). Furthermore, wound healing and transwell assays showed that SREBP-1 knockdown prominently inhibited cell migration and invasion in both HepG2 and MHCC97L cells (p < 0.05). These results suggest that SREBP-1 may serve as a prognostic marker in HCC and may promote tumor progression by promoting cell growth and metastasis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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12 pages, 474 KiB

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Combined Elevation of microRNA-196a and microRNA-196b in Sera Predicts Unfavorable Prognosis in Patients with Osteosarcomas

by Chun Zhang, Cong Yao, Haopeng Li, Guoyu Wang and Xijng He

Int. J. Mol. Sci. 2014, 15(4), 6544-6555; https://doi.org/10.3390/ijms15046544 - 17 Apr 2014

Cited by 60 | Viewed by 7161

Abstract

Aim: To investigate whether the aberrant expression of microRNA (miR)-196a and miR-196b can be used as potential prognostic markers of human osteosarcoma. Methods: Quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis was performed to detect the expression levels of miR-196a and miR-196b in [...] Read more.

Aim: To investigate whether the aberrant expression of microRNA (miR)-196a and miR-196b can be used as potential prognostic markers of human osteosarcoma. Methods: Quantitative real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) analysis was performed to detect the expression levels of miR-196a and miR-196b in osteosarcoma tissues and patients’ sera. Results: Expression levels of miR-196a and miR-196b in osteosarcoma tissues were both significantly higher than those in noncancerous bone tissues (both p < 0.001), in line with which, the serum levels of the two miRNAs were also markedly upregulated in patients with osteosarcomas compared with healthy controls (both p < 0.001). Then, the elevation of serum miR-196a and miR-196b levels both more frequently occurred in osteosarcoma patients with high tumor grade (p = 0.008 and 0.01, respectively), positive metastasis (p = 0.001 and 0.006, respectively) and recurrence (p = 0.001 and 0.006, respectively). Moreover, high serum miR-196a, high serum miR-196b and conjoined expression of miR-196a/miR-196b were all independent prognostic factors for OS (overall survival) and DFS (disease-free survival) of osteosarcoma patients. Conclusion: Our present data indicate the involvement of miR-196a and miR-196b upregulation in the pathogenesis of osteosarcoma. More importantly, the altered levels of circulating miR-196a and miR-196b might have great potential to serve as novel and non-invasive prognostic factors for this malignancy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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12 pages, 439 KiB

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Beclin 1 Expression in Ovarian Tissues and Its Effects on Ovarian Cancer Prognosis

by Mingbo Cai, Zhenhua Hu, Juanjuan Liu, Jian Gao, Chuan Liu, Dawo Liu, Mingzi Tan, Danye Zhang and Bei Lin

Int. J. Mol. Sci. 2014, 15(4), 5292-5303; https://doi.org/10.3390/ijms15045292 - 26 Mar 2014

Cited by 60 | Viewed by 8624

Abstract

Beclin 1 is an autophagy-associated protein involved in apoptosis and drug resistance, as well as various malignancies. We investigated the expression of Beclin 1 protein in ovarian epithelial tissues and correlated it with the prognosis of ovarian cancer. Beclin 1 protein expression was [...] Read more.

Beclin 1 is an autophagy-associated protein involved in apoptosis and drug resistance, as well as various malignancies. We investigated the expression of Beclin 1 protein in ovarian epithelial tissues and correlated it with the prognosis of ovarian cancer. Beclin 1 protein expression was determined using immunohistochemistry in 148 patients with ovarian epithelial cancer, 26 with ovarian borderline tumor, 25 with benign ovarian tumor, and 30 with normal ovarian tissue. The relationships between Beclin 1 protein expression and ovarian cancer pathological characteristics were analyzed. The risk factors for ovarian cancer prognosis were analyzed using Cox’s regression model. A survival curve was plotted from the follow-up data of 93 patients with ovarian cancer to analyze the effects of Beclin 1 expression on the prognosis of ovarian cancer. The positive rates of Beclin 1 were significantly higher in ovarian epithelial cancer (148) and borderline tumor (26) than in benign ovarian tumor (25) or normal ovarian tissue (30) (all p < 0.001). The surgical stage and Beclin 1 expression were both independent risk factors for ovarian cancer prognosis (both p < 0.05). Patients with high Beclin 1 levels showed better survival than those with low Beclin 1 levels (p = 0.009). Beclin 1 protein is upregulated in ovarian epithelial cancer and is a prognostic factor of ovarian cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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11 pages, 186 KiB

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Polymorphisms in DNA Repair Genes and Susceptibility to Glioma in a Chinese Population

by Wei-Ran Pan, Gang Li and Jun-Hong Guan

Int. J. Mol. Sci. 2013, 14(2), 3314-3324; https://doi.org/10.3390/ijms14023314 - 5 Feb 2013

Cited by 37 | Viewed by 6885

Abstract

The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and X-ray repair cross-complementing group 1 (XRCC1) genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms [...] Read more.

The excision repair cross-complementing rodent repair deficiency complementation group 1 (ERCC1), and X-ray repair cross-complementing group 1 (XRCC1) genes appear to protect mammalian cells from the harmful effects of ionizing radiation. We conducted a large case-control study to investigate the association of polymorphisms in ERCC1 C118T, ERCC1 C8092A, XRCC1 A194T, XRCC1 A194T, and XRCC3 C241T, with glioma risk in a Chinese population. Five single nucleotide polymorphisms (SNPs) were genotyped, using the MassARRAY IPLEX platform, in 443 glioma cases and 443 controls. Association analyses based on an χ² test and binary logistic regression were performed to determine the odds ratio (OR) and a 95% confidence interval (95% CI) for each SNP. For XRCC1 Arg194Trp, the variant genotype T/T was strongly associated with a lower risk of glioma cancer when compared with the wild type C/C (OR = 2.45, 95% CI = 1.43–4.45). Individuals carrying the XRCC1 399A allele had an increased risk of glioma (OR = 1.33, 95% CI = 1.02–1.64). The XRCC3 241T/T genotype was associated with a strong increased glioma risk (OR = 3.78, 95% CI = 1.86–9.06). Further analysis of the interactions of two susceptibility-associated SNPs, XRCC1 Arg194Trp and XRCC3 Thr241Met, showed that the combination of the XRCC1 194T and XRCC3 241T alleles brought a large increase in glioma risk (OR = 2.75, 95% CI = 1.54–4.04). XRCC1 Arg194Trp, XRCC1 Arg399Gln, and XRCC3 C241T, appear to be associated with susceptibility to glioma in a Chinese population. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

13 pages, 1888 KiB

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Anticancer Effects of Bufalin on Human Hepatocellular Carcinoma HepG2 Cells: Roles of Apoptosis and Autophagy

by Qing Miao, Lin-Lin Bi, Xin Li, Shan Miao, Jin Zhang, Song Zhang, Qian Yang, Yan-Hua Xie, Jian Zhang and Si-Wang Wang

Int. J. Mol. Sci. 2013, 14(1), 1370-1382; https://doi.org/10.3390/ijms14011370 - 11 Jan 2013

Cited by 89 | Viewed by 14633

Abstract

The traditional Chinese medicine bufalin, extracted from toad’s skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type I programmed cell death (PCD). However, type [...] Read more.

The traditional Chinese medicine bufalin, extracted from toad’s skin, has been demonstrated to exert anticancer activities in various kinds of human cancers. The mechanisms of action lie in its capacity to induce apoptosis, or termed type I programmed cell death (PCD). However, type II PCD, or autophagy, participates in cancer proliferation, progression, and relapse, as well. Recent studies on autophagy seem to be controversial because of the dual roles of autophagy in cancer survival and death. In good agreement with previous studies, we found that 100 nM bufalin induced extensive HepG2 cell apoptosis. However, we also noticed bufalin triggered autophagy and enhanced Beclin-1 expression, LC3-I to LC3-II conversion, as well as decreased p62 expression and mTOR signaling activation in HepG2 cells. Blockage of autophagy by selective inhibitor 3-MA decreased apoptotic ratio in bufalin-treated HepG2 cells, suggesting a proapoptotic role of bufalin-induced autophagy. Furthermore, we investigated the underlying mechanisms of bufalin-induced autophagy. Bufalin treatment dose-dependently promoted AMPK phosphorylation while AMPK inhibition by compound C significantly attenuated bufalin-induced autophagy. Taken together, we report for the first time that bufalin induces HepG2 cells PCD, especially for autophagy, and the mechanism of action is, at least in part, AMPK-mTOR dependent. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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12 pages, 458 KiB

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Modulation of MDR1 and MRP3 Gene Expression in Lung Cancer Cells after Paclitaxel and Carboplatin Exposure

by Consolación Melguizo, Jose Prados, Raquel Luque, Raúl Ortiz, Octavio Caba, Pablo J. Álvarez, Beatriz Gonzalez and Antonia Aranega

Int. J. Mol. Sci. 2012, 13(12), 16624-16635; https://doi.org/10.3390/ijms131216624 - 5 Dec 2012

Cited by 21 | Viewed by 7816

Abstract

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand [...] Read more.

Carboplatin-paclitaxel is a reference regimen in the treatment of locally advanced or disseminated non-small cell lung cancer (NSCLC). This paper discusses the multidrug resistance developed with this drug combination, which is one of the major obstacles to successful treatment. In order to understand and overcome the drug resistance pattern of NSCLC after carboplatin plus paclitaxel exposure, levels of mRNA expression of multidrug resistance 1 (MDR1) and multidrug resistance-associated protein 3 (MRP3) were investigated in primary NSCLC cell lines (A-549 and A-427) and a metastasis-derived NSCLC cell line (NODO). Our results showed that exposure of the three NSCLC lines to plasma concentrations of paclitaxel (5 μM) produced an increase in MDR1 expression, while MRP3 showed no alteration in expression. By contrast, the same cells exposed to carboplatin plasma concentrations (30 μM) showed overexpression of MRP3. In these cells, MDR1 showed no expression changes. Interestingly, the combination of both paclitaxel and carboplatin caused increased expression of the MDR1 drug resistance gene rather than the individual treatments. These results suggest that carboplatin and paclitaxel may induce drug resistance mediated by MDR1 and MRP3, which may be enhanced by the simultaneous use of both drugs. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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17 pages, 453 KiB

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Targeting Death Receptor TRAIL-R2 by Chalcones for TRAIL-Induced Apoptosis in Cancer Cells

by Ewelina Szliszka, Dagmara Jaworska, Małgorzata Ksek, Zenon P. Czuba and Wojciech Król

Int. J. Mol. Sci. 2012, 13(11), 15343-15359; https://doi.org/10.3390/ijms131115343 - 20 Nov 2012

Cited by 58 | Viewed by 8818

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune [...] Read more.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells without toxicity to normal cells. TRAIL binds to death receptors, TRAIL-R1 (DR4) and TRAIL-R2 (DR5) expressed on cancer cell surface and activates apoptotic pathways. Endogenous TRAIL plays an important role in immune surveillance and defense against cancer cells. However, as more tumor cells are reported to be resistant to TRAIL mediated death, it is important to search for and develop new strategies to overcome this resistance. Chalcones can sensitize cancer cells to TRAIL-induced apoptosis. We examined the cytotoxic and apoptotic effects of TRAIL in combination with four chalcones: chalcone, isobavachalcone, licochalcone A and xanthohumol on HeLa cancer cells. The cytotoxicity was measured by MTT and LDH assays. The apoptosis was detected using annexin V-FITC staining by flow cytometry and fluorescence microscopy. Death receptor expression was analyzed using flow cytometry. The decreased expression of death receptors in cancer cells may be the cause of TRAIL-resistance. Chalcones enhance TRAIL-induced apoptosis in HeLa cells through increased expression of TRAIL-R2. Our study has indicated that chalcones augment the antitumor activity of TRAIL and confirm their cancer chemopreventive properties. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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11 pages, 172 KiB

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Genomic Polymorphism of Human Papillomavirus Type 52 in Women from Northeast China

by Zhengrong Sun, Zhitao Lu, Jianhua Liu, Guili Wang, Weiqiang Zhou, Lianxia Yang, Chao Liu and Qiang Ruan

Int. J. Mol. Sci. 2012, 13(11), 14962-14972; https://doi.org/10.3390/ijms131114962 - 15 Nov 2012

Cited by 12 | Viewed by 5930

Abstract

Human papillomavirus (HPV) 52 is an oncogenic HPV type prevalent in Asia. The aim of the study was to analyze HPV 52 genetic variations in women from Northeast China. To explore the intratypic variants of HPV 52, the genomic regions of L1, [...] Read more.

Human papillomavirus (HPV) 52 is an oncogenic HPV type prevalent in Asia. The aim of the study was to analyze HPV 52 genetic variations in women from Northeast China. To explore the intratypic variants of HPV 52, the genomic regions of L1, E6, E7 and long control region (LCR) of HPV 52, which have been identified in women from Northeast China by HPV GenoArray test, were analyzed. Twenty-five mutations were identified in the regions examined. Of the mutations found in the L1 gene, three novel nonsynonymous mutations of C5640T, A5641T and G5642A were located within the region that encodes the binding domain of neutralizing antibodies against HPV 52. Although four variations were identified in HPV 52 E6 and E7 genes, no significant association was found between the mutations and the cytological lesion of the patients. Eight mutations, including a novel CTT7681–7683 deletion, found in the LCR of HPV 52 encompassed the known transcription binding sites, which may possibly affect the transcription of the oncogenic genes of E6 and E7. The most prevalent HPV 52 variant in women from northeastern China belongs to clade L1-LN-A. The genetic variations of HPV 52, including three novel nonsynonymous mutations of C5640T, A5641T and G5642A in the L1 gene and a novel CTT7681–7683 deletion in the LCR, were first documented in strains from women in Northeast China. The statistical result showed no associations between the variants and the severities of the infected women. These findings provide new data regarding gene variations of HPV 52. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

12 pages, 1155 KiB

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Role of Btg2 in the Progression of a PDGF-Induced Oligodendroglioma Model

by Irene Appolloni, Sebastiano Curreli, Sara Caviglia, Manuela Barilari, Eleonora Gambini, Aldo Pagano and Paolo Malatesta

Int. J. Mol. Sci. 2012, 13(11), 14667-14678; https://doi.org/10.3390/ijms131114667 - 12 Nov 2012

Cited by 8 | Viewed by 6602

Abstract

Tumor progression is a key aspect in oncology. Not even the overexpression of a powerful oncogenic stimulus such as platelet derived growth factor-B (PDGF-B) is sufficient per se to confer full malignancy to cells. In previous studies we showed that neural progenitors overexpressing [...] Read more.

Tumor progression is a key aspect in oncology. Not even the overexpression of a powerful oncogenic stimulus such as platelet derived growth factor-B (PDGF-B) is sufficient per se to confer full malignancy to cells. In previous studies we showed that neural progenitors overexpressing PDGF-B need to undergo progression to acquire the capability to give rise to secondary tumor following transplant. By comparing the expression profile of PDGF-expressing cells before and after progression, we found that progressed tumors consistently downregulate the expression of the antiproliferative gene Btg2. We therefore tested whether the downregulation of Btg2 is sufficient and necessary for glioma progression with loss and gain of function experiments. Our results show that downregulation of Btg2 is not sufficient but is necessary for tumor progression since the re-introduction of Btg2 in fully progressed tumors dramatically impairs their gliomagenic potential. These results suggest an important role of Btg2 in glioma progression. Accordingly with this view, the analysis of public datasets of human gliomas showed that reduced level of Btg2 expression correlates with a significantly worse prognosis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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15 pages, 985 KiB

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Protein Profiling of Blood Samples from Patients with Hereditary Leiomyomatosis and Renal Cell Cancer by Surface-Enhanced Laser Desorption/Ionization Time-of-Flight Mass Spectrometry

by Takao Kamai, Naohisa Tomosugi, Hideyuki Abe, Yasushi Kaji, Tetsunari Oyama and Ken-Ichiro Yoshida

Int. J. Mol. Sci. 2012, 13(11), 14518-14532; https://doi.org/10.3390/ijms131114518 - 8 Nov 2012

Cited by 11 | Viewed by 6981

Abstract

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an extremely rare syndrome with autosomal dominant inheritance. HLRCC is characterized by a predisposition to leiomyomas of the skin and the uterus as well as renal cell carcinoma. The disease-related gene has been identified as [...] Read more.

Hereditary leiomyomatosis and renal cell cancer (HLRCC) is an extremely rare syndrome with autosomal dominant inheritance. HLRCC is characterized by a predisposition to leiomyomas of the skin and the uterus as well as renal cell carcinoma. The disease-related gene has been identified as fumarate hydratase (fumarase, FH), which encodes an enzyme involved in the mitochondrial tricarboxylic acid cycle. Protein profiling may give some insight into the molecular pathways of HLRCC. Therefore, we performed protein profiling of blood samples from HLRCC patients, their family members, and healthy volunteers, using surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF MS) coupled with IMAC-Cu chips. For hierarchical clustering analysis, we used the 45 peaks that revealed significant differences in single-marker analysis over the range from 1500 to 15,000 m/z. Heat map analysis based on the results of clustering distinguished the HLRCC kindred from non-HLRCC subjects with a sensitivity of 94% and a specificity of 90%. SELDI-TOF MS profiling of blood samples can be applied to identify patients with HLRCC and to assess specific molecular mechanisms involved in this condition. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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17 pages, 2741 KiB

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Quantum Dots-Based Immunofluorescent Imaging of Stromal Fibroblasts Caveolin-1 and Light Chain 3B Expression and Identification of Their Clinical Significance in Human Gastric Cancer

by Yuyu He, Xianda Zhao, Jun Gao, Lifang Fan, Guifang Yang, William Chi-shing Cho and Honglei Chen

Int. J. Mol. Sci. 2012, 13(11), 13764-13780; https://doi.org/10.3390/ijms131113764 - 24 Oct 2012

Cited by 31 | Viewed by 7867

Abstract

Caveolin-1 (Cav-1) expression deficiency and autophagy in tumor stromal fibroblasts (hereafter fibroblasts) are involved in tumor proliferation and progression, particularly in breast and prostate cancer. The aim of this study was to detect the expression of fibroblastic Cav-1 and LC3B, markers of autophagy, [...] Read more.

Caveolin-1 (Cav-1) expression deficiency and autophagy in tumor stromal fibroblasts (hereafter fibroblasts) are involved in tumor proliferation and progression, particularly in breast and prostate cancer. The aim of this study was to detect the expression of fibroblastic Cav-1 and LC3B, markers of autophagy, in gastric cancer (GC) and to analyze their clinical significances. Furthermore, because Epstein-Barr virus (EBV)-associated GC (EBVaGC) is a unique subtype of GC; we compared the differential expression of fibroblastic Cav-1 and LC3B in EBVaGC and non-EBVaGC. Quantum dots (QDs)-based immunofluorescence histochemistry was used to examine the expression of fibroblastic Cav-1 and LC3B in 118 cases of GC with adequate stroma. QDs-based double immunofluorescence labeling was performed to detect the coexpression of Cav-1 and LC3B proteins. EBV-encoded small RNA was detected by QDs-based fluorescence in situ hybridization to identify EBVaGC. Multivariate analysis indicated that low fibroblastic Cav-1 level was an independent prognosticator (p = 0.029) that predicted poorer survival of GC patients. Positive fibroblastic LC3B was correlated with lower invasion (p = 0.032) and was positively associated with Cav-1 expression (r = 0.432, p < 0.001). EBV infection did not affect fibroblastic Cav-1 and LC3B expression. In conclusion, positive fibroblastic LC3B correlates with lower invasion, and low expression of fibroblastic Cav-1 is a novel predictor of poor GC prognosis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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20 pages, 1320 KiB

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Altered DNA Binding and Amplification of Human Breast Cancer Suppressor Gene BRCA1 Induced by a Novel Antitumor Compound, [Ru(η⁶-p-phenylethacrynate)Cl₂(pta)]

by Korawan Chakree, Chitchamai Ovatlarnporn, Paul J. Dyson and Adisorn Ratanaphan

Int. J. Mol. Sci. 2012, 13(10), 13183-13202; https://doi.org/10.3390/ijms131013183 - 15 Oct 2012

Cited by 22 | Viewed by 9380

Abstract

The ruthenium-based complex [Ru(η⁶-p-phenylethacrynate)Cl₂(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the [...] Read more.

The ruthenium-based complex [Ru(η⁶-p-phenylethacrynate)Cl₂(pta)] (pta = 1,3,5-triaza-7-phosphatricyclo-[3.3.1.1]decane), termed ethaRAPTA, is an interesting antitumor compound. The elucidation of the molecular mechanism of drug activity is central to the drug development program. To this end, we have characterized the ethaRAPTA interaction with DNA, including probing the sequence specific modified DNA structural stability and DNA amplification using the breast cancer suppressor gene 1 (BRCA1) of human breast and colon adenocarcinoma cell lines as models. The preference of ethaRAPTA base binding is in the order A > G > T > C. Once modified, the ethaRAPTA-induced BRCA1 structure has higher thermal stability than the modified equivalents of its related compound, RAPTA-C. EthaRAPTA exhibits a higher efficiency than RAPTA-C in inhibiting BRCA1 amplification. With respect to both compounds, the inhibition of BRCA1 amplification is more effective in an isolated system than in cell lines. These data provide evidence that will help to understand the process of elucidating the pathways involved in the response induced by ethaRAPTA. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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19 pages, 1905 KiB

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Binding of the Phage Display Derived Peptide CaIX-P1 on Human Colorectal Carcinoma Cells Correlates with the Expression of Carbonic Anhydrase IX

by Vasileios Askoxylakis, Volker Ehemann, Shoaib Rana, Susanne Krämer, Nuh N. Rahbari, Jürgen Debus and Uwe Haberkorn

Int. J. Mol. Sci. 2012, 13(10), 13030-13048; https://doi.org/10.3390/ijms131013030 - 11 Oct 2012

Cited by 9 | Viewed by 7675

Abstract

Phage display represents an attractive screening strategy for the identification of novel, specific binding ligands that could be used for tumor targeting. Recently, a new peptide (CaIX-P1) with affinity for human carbonic anhydrase IX (CAIX) was identified and evaluated. The aim of the [...] Read more.

Phage display represents an attractive screening strategy for the identification of novel, specific binding ligands that could be used for tumor targeting. Recently, a new peptide (CaIX-P1) with affinity for human carbonic anhydrase IX (CAIX) was identified and evaluated. The aim of the present study is to characterize the properties of CaIX-P1 for targeting human colorectal carcinoma and investigate the correlation of peptide binding with the expression of carbonic anhydrase IX. Human colorectal carcinoma HCT116 and HT29 cells were investigated for CAIX expression using Western Blot analysis. Binding and competition studies of ¹²⁵I-radiolabeled CaIX-P1 were performed on HCT116 cells in vitro. FACS analysis and fluorescence microscopy studies were carried out after cell incubation with fluorescein-labeled CaIX-P1 and rhodamine-labeled anti-human CAIX-mAb. Our studies revealed an enhanced in vitro expression of carbonic anhydrase IX in HCT116 and HT29 cells with increasing cell density. Binding of ¹²⁵I-labeled-CaIX-P1 on HCT116 cells increased with increasing cell density and correlated to the CAIX expression. FACS analysis demonstrated a correlation of cell labeling between FITC-CaIX-P1 and rhodamine-labeled anti-CAIX-mAb in both HCT116 and HT29 cells. The results of our study indicate that the phage display identified peptide CaIX-P1 might be an attractive candidate for the development of a ligand targeting CAIX in colorectal cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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14 pages, 966 KiB

Open AccessArticle

Effects of Genetically Engineered Stem Cells Expressing Cytosine Deaminase and Interferon-Beta or Carboxyl Esterase on the Growth of LNCaP Prostate Cancer Cells

by Bo-Rim Yi, Kyung-A. Hwang, Yun-Bae Kim, Seung U. Kim and Kyung-Chul Choi

Int. J. Mol. Sci. 2012, 13(10), 12519-12532; https://doi.org/10.3390/ijms131012519 - 28 Sep 2012

Cited by 15 | Viewed by 7616

Abstract

The risk of prostate cancer has been increasing in men by degrees. To develop a new prostate cancer therapy, we used a stem cell-derived gene directed prodrug enzyme system using human neural stem cells (hNSCs) that have a tumor-tropic effect. These hNSCs were [...] Read more.

The risk of prostate cancer has been increasing in men by degrees. To develop a new prostate cancer therapy, we used a stem cell-derived gene directed prodrug enzyme system using human neural stem cells (hNSCs) that have a tumor-tropic effect. These hNSCs were transduced with the therapeutic genes for bacterial cytosine deaminase (CD), alone or in combination with the one encoding human interferon-beta (IFN-β) or rabbit carboxyl esterase (CE) to generate HB1.F3.CD, HB1.F3.CD.IFN-β, and HB1.F3.CE cells, respectively. CD enzyme can convert the prodrug 5-fluorocytosine (5-FC) into the activated form 5-fluorouracil (5-FU). In addition, CE enzyme can convert the prodrug CPT-11 into a toxic agent, SN-38. In our study, the human stem cells were found to migrate toward LNCaP human prostate cancer cells rather than primary cells. This phenomenon may be due to interactions between chemoattractant ligands and receptors, such as VEGF/VEGFR2 and SCF/c-Kit, expressed as cancer and stem cells, respectively. The HB1.F3.CE, HB.F3.CD, or HB1.F3.CD.IFN-β cells significantly reduced the LNCaP cell viability in the presence of the prodrugs 5-FC or CPT-11. These results indicate that stem cells expressing therapeutic genes can be used to develop a new strategy for selectively treating human prostate cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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17 pages, 493 KiB

Open AccessArticle

Anti-Epidermal Growth Factor Receptor (EGFR) Antibodies Overcome Resistance of Ovarian Cancer Cells to Targeted Therapy and Natural Cytotoxicity

by Nina Gottschalk, Rainer Kimmig, Stephan Lang, Mahavir Singh and Sven Brandau

Int. J. Mol. Sci. 2012, 13(9), 12000-12016; https://doi.org/10.3390/ijms130912000 - 20 Sep 2012

Cited by 25 | Viewed by 10082

Abstract

The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine [...] Read more.

The poor outcome of advanced ovarian cancer under conventional therapy stimulated the exploration of new strategies to improve therapeutic efficacy. In our preclinical in vitro study we investigated a combination of targeted therapy and immunotherapy. Combination treatment with the anti-EGFR-antibody Cetuximab, related tyrosine kinase inhibitors (TKI) and cytolytic NK cells was tested against different ovarian cancer cell lines and primary tumour cells cultured from patient ascites. We found that selected ovarian cancer cells were susceptible to cetuximab and anti-EGFR-TKI-treatment, while the majority of cell lines were resistant to single or combination treatment with both substances. In addition, most ovarian cancer cells displayed low susceptibility to natural cytotoxicity of unstimulated NK cells. Notably, NK cytotoxicity against resistant ovarian cancer cells could be effectively enhanced by addition of Cetuximab mediating antibody-dependent cellular cytotoxicity (ADCC). Neither natural cytotoxicity nor ADCC of NK cells were negatively affected by the presence of TKIs. ADCC could be further increased when NK cells were pre-stimulated with monocytes and the immunostimulatory mycobacterial protein PstS-1. Our data suggest that targeted antibody therapy could be beneficial even against resistant tumour cells by augmenting supplementary cytolytic NK functions. Future studies should evaluate the combination of targeted therapy and immunotherapeutic approaches in patients with advanced ovarian cancer being resistant to standard treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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13 pages, 471 KiB

Open AccessArticle

Effects of Sorafenib on C-Terminally Truncated Androgen Receptor Variants in Human Prostate Cancer Cells

by Friedemann Zengerling, Wolfgang Streicher, Andres J. Schrader, Mark Schrader, Bianca Nitzsche, Marcus V. Cronauer and Michael Höpfner

Int. J. Mol. Sci. 2012, 13(9), 11530-11542; https://doi.org/10.3390/ijms130911530 - 14 Sep 2012

Cited by 16 | Viewed by 7495

Abstract

Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression [...] Read more.

Recent evidence suggests that the development of castration resistant prostate cancer (CRPCa) is commonly associated with an aberrant, ligand-independent activation of the androgen receptor (AR). A putative mechanism allowing prostate cancer (PCa) cells to grow under low levels of androgens, is the expression of constitutively active, C-terminally truncated AR lacking the AR-ligand binding domain (LBD). Due to the absence of a LBD, these receptors, termed ARΔLBD, are unable to respond to any form of anti-hormonal therapies. In this study we demonstrate that the multikinase inhibitor sorafenib inhibits AR as well as ARΔLBD-signalling in CRPCa cells. This inhibition was paralleled by proteasomal degradation of the AR- and ARΔLBD-molecules. In line with these observations, maximal antiproliferative effects of sorafenib were achieved in AR and ARΔLBD-positive PCa cells. The present findings warrant further investigations on sorafenib as an option for the treatment of advanced AR-positive PCa. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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19 pages, 733 KiB

Open AccessArticle

Tissue Microarray-Based Evaluation of Chromatin Assembly Factor-1 (CAF-1)/p60 as Tumour Prognostic Marker

by Massimo Mascolo, Gennaro Ilardi, Francesco Merolla, Daniela Russo, Maria Luisa Vecchione, Gaetano De Rosa and Stefania Staibano

Int. J. Mol. Sci. 2012, 13(9), 11044-11062; https://doi.org/10.3390/ijms130911044 - 5 Sep 2012

Cited by 24 | Viewed by 7584

Abstract

In this study we aimed to confirm the emerging role of Chromatin Assembly Factor 1 (CAF-1 p60) as a new proliferation and prognostic marker for cancer and to test the usefulness of the tissue microarray technique (TMA) for CAF-1 p60 rapid screening in [...] Read more.

In this study we aimed to confirm the emerging role of Chromatin Assembly Factor 1 (CAF-1 p60) as a new proliferation and prognostic marker for cancer and to test the usefulness of the tissue microarray technique (TMA) for CAF-1 p60 rapid screening in several human malignancies. CAF-1 is a histone chaperone, regulating chromatin dynamics during DNA replication and repair in eukaryotics. TMA is a powerful high-throughput methodology in the study of cancer, allowing simultaneous assessment of different biomarkers within large numbers of tissue specimens. We generated TMA taking 3 mm diameter-core biopsies from oral squamous cell carcinoma, prostate cancer, salivary gland tumours and skin melanoma specimens, which had been previously tested for CAF-1 p60 on routine tissue sections. We also analysed, for the first time, 30 larynx and 30 skin squamous cell carcinomas. CAF-1 p60 resulted over-expressed in both the tissue sections and the TMA specimens, with the highest levels of expression in tumours which were more aggressive and metastasizing. Notably, a high degree of agreement was found between the CAF-1 p60 assessment on TMAs and on routine tissue sections. Our findings confirm the prognostic role of CAF-1 p60 and indicate TMA as a really advantageous method for CAF-1 p60 immunohistochemical screening, allowing savings on both tissue quantity and operator-time. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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11 pages, 521 KiB

Open AccessArticle

NAD(P)H:Quinone Oxidoreductase 1 (NQO1) P187S Polymorphism and Prostate Cancer Risk in Caucasians

by Christine G. Stoehr, Elke Nolte, Sven Wach, Wolf F. Wieland, Ferdinand Hofstaedter, Arndt Hartmann and Robert Stoehr

Int. J. Mol. Sci. 2012, 13(9), 10959-10969; https://doi.org/10.3390/ijms130910959 - 31 Aug 2012

Cited by 15 | Viewed by 7441

Abstract

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A “C” to “T” transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in [...] Read more.

NAD(P)H:quinone oxidoreductase 1 (NQO1) catalyses the reduction of quinoid compounds to hydroquinones, preventing the generation of free radicals and reactive oxygen. A “C” to “T” transversion at position 609 of NQO1, leading to a nonsynonymous amino acid change (Pro187Ser, P187S), results in an altered enzyme activity. No NQO1 protein activity was detected in NQO1 ⁶⁰⁹TT genotype, and low to intermediate activity was detected in NQO1 ⁶⁰⁹CT genotype compared with ⁶⁰⁹CC genotype. Thus, this polymorphism may result in altered cancer predisposition. For prostate cancer, only sparse data are available. We therefore analyzed the distribution of the NQO1 P187S SNP (single nucleotide polymorphism) in prostate cancer patients and a healthy control group. Allelic variants were determined using RFLP analysis. Overall, 232 patients without any malignancy and 119 consecutive prostate cancer patients were investigated. The genotype distribution in our cohorts followed the Hardy–Weinberg equilibrium in cases and controls. The distribution of the NQO1 codon 187 SNP did not differ significantly between prostate cancer patients and the control group (p = 0.242). There was also no association between the allelic variants and stage or Gleason score of the tumors. The NQO1 P187S SNP was not significantly associated with an increased prostate cancer risk in our cohorts. The SNP has also no influence on histopathological characteristics of the tumors. A combined analysis of all available data from published European studies also showed no significant differences in the genotype distribution between controls and prostate cancer patients. Our data suggest a minor role of the NQO1 nucleotide 609 polymorphism in prostate carcinogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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14 pages, 1035 KiB

Open AccessArticle

Combined Treatment with an Oncolytic Adenovirus and Antitumor Activity of Vincristine against Retinoblastoma Cells

by Xin Song, Haibo Wang, Renbing Jia, Biyun Cun, Xiaoping Zhao, Yixiong Zhou, Xiaofang Xu, Guanxiang Qian, Shengfang Ge and Xianqun Fan

Int. J. Mol. Sci. 2012, 13(9), 10736-10749; https://doi.org/10.3390/ijms130910736 - 27 Aug 2012

Cited by 12 | Viewed by 7069

Abstract

Treatment trends of retinoblastoma (RB) have gradually evolved from eye enucleation and external radiation to local treatment. Combined treatment with an oncolytic virus and chemotherapy is currently a new method in RB treatment. To investigate the therapeutic effect of oncolytic adenovirus SG600 in [...] Read more.

Treatment trends of retinoblastoma (RB) have gradually evolved from eye enucleation and external radiation to local treatment. Combined treatment with an oncolytic virus and chemotherapy is currently a new method in RB treatment. To investigate the therapeutic effect of oncolytic adenovirus SG600 in combination with vincristine (VCR) on retinoblastoma in vitro, the cell viability, cell cycle effects and apoptotic activity of HXO-RB₄₄ cells treated with SG600, VCR or SG600 plus VCR were measured using a cell counting kit-8-based procedure and flow cytometry. Western blot analysis for Akt, p-Akt, p-p53 and p-Rb protein was performed to investigate the underlying mechanisms of combined therapy. The combination therapy exerted a synergistic antitumor effect via a type of G₂/M and S phase arrest rather than the induction of apoptosis. The combination of VCR and SG600 further reduced Akt phosphorylation compared with cells treated with VCR alone, suggesting that SG600 could overcome chemoresistance, perhaps by down-regulating Akt in RB cells. An increase in the expression of p-p53 and decrease in p-Rb expression in HXO-RB₄₄ after co-treatment might be associated with cell cycle block. Western blot examination revealed that VCR might enhance SG600 replication. These results suggest that viro-chemo combination therapy is a feasible and potentially promising approach for the treatment of retinoblastoma. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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17 pages, 878 KiB

Open AccessArticle

Helicobacter pylori Disrupts Host Cell Membranes, Initiating a Repair Response and Cell Proliferation

by Li-Ling Lin, Hsuan-Cheng Huang, Satoshi Ogihara, Jin-Town Wang, Meng-Chuan Wu, Paul L. McNeil, Chiung-Nien Chen and Hsueh-Fen Juan

Int. J. Mol. Sci. 2012, 13(8), 10176-10192; https://doi.org/10.3390/ijms130810176 - 15 Aug 2012

Cited by 17 | Viewed by 8747

Abstract

Helicobacter pylori (H. pylori), the human stomach pathogen, lives on the inner surface of the stomach and causes chronic gastritis, peptic ulcer, and gastric cancer. Plasma membrane repair response is a matter of life and death for human cells against physical [...] Read more.

Helicobacter pylori (H. pylori), the human stomach pathogen, lives on the inner surface of the stomach and causes chronic gastritis, peptic ulcer, and gastric cancer. Plasma membrane repair response is a matter of life and death for human cells against physical and biological damage. We here test the hypothesis that H. pylori also causes plasma membrane disruption injury, and that not only a membrane repair response but also a cell proliferation response are thereby activated. Vacuolating cytotoxin A (VacA) and cytotoxin-associated gene A (CagA) have been considered to be major H. pylori virulence factors. Gastric cancer cells were infected with H. pylori wild type (vacA+/cagA+), single mutant (ΔvacA or ΔcagA) or double mutant (ΔvacA/ΔcagA) strains and plasma membrane disruption events and consequent activation of membrane repair components monitored. H. pylori disrupts the host cell plasma membrane, allowing localized dye and extracellular Ca²⁺ influx. Ca²⁺-triggered members of the annexin family, A1 and A4, translocate, in response to injury, to the plasma membrane, and cell surface expression of an exocytotic maker of repair, LAMP-2, increases. Additional forms of plasma membrane disruption, unrelated to H. pylori exposure, also promote host cell proliferation. We propose that H. pylori activation of a plasma membrane repair is pro-proliferative. This study might therefore provide new insight into potential mechanisms of H. pylori-induced gastric carcinogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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13 pages, 1240 KiB

Open AccessArticle

MicroRNA-125b Functions as a Tumor Suppressor in Hepatocellular Carcinoma Cells

by Hong-Yan Jia, Yu-Xuan Wang, Wen-Ting Yan, Hui-Yu Li, Yan-Zhang Tian, Shi-Ming Wang and Hao-Liang Zhao

Int. J. Mol. Sci. 2012, 13(7), 8762-8774; https://doi.org/10.3390/ijms13078762 - 16 Jul 2012

Cited by 76 | Viewed by 8702

Abstract

MicroRNAs (miRNAs) are important regulators of multiple cellular processes, and the deregulation of miRNA is a common event in diverse human diseases, particularly cancer. However, the mechanisms underlying the relationship between disordered miRNA expression and tumorigenesis have remained largely unknown. In this study, [...] Read more.

MicroRNAs (miRNAs) are important regulators of multiple cellular processes, and the deregulation of miRNA is a common event in diverse human diseases, particularly cancer. However, the mechanisms underlying the relationship between disordered miRNA expression and tumorigenesis have remained largely unknown. In this study, we demonstrated the down-regulation of miR-125b in hepatocellular carcinoma (HCC) tissues and HCC cell lines by Northern blot and quantitative RT-PCR analyses. The ectopic expression of miR-125b reduced the cellular proliferation and cell cycle progression of HCC cells by targeting Mcl-1 and IL6R. Furthermore, the miR-125b-induced inhibition of cell proliferation was rescued by the expression of Mcl-1 or IL6R variants that lacked 3' UTRs. Thus, this study revealed the differential expression of miR-125b in HCC cells and elucidated its potential as a tumor suppressor in HCC development. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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18 pages, 2305 KiB

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Chemopreventive Efficacy of Atorvastatin against Nitrosamine-Induced Rat Bladder Cancer: Antioxidant, Anti-Proliferative and Anti-Inflammatory Properties

by Belmiro Parada, Flávio Reis, Ângela Pinto, José Sereno, Maria Xavier-Cunha, Paula Neto, Petronila Rocha-Pereira, Alfredo Mota, Arnaldo Figueiredo and Frederico Teixeira

Int. J. Mol. Sci. 2012, 13(7), 8482-8499; https://doi.org/10.3390/ijms13078482 - 9 Jul 2012

Cited by 28 | Viewed by 8955

Abstract

To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) Control: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: [...] Read more.

To investigate the anti-carcinogenic effects of Atorvastatin (Atorva) on a rat bladder carcinogenesis model with N-butyl-N-(4-hydroxibutil)nitrosamine (BBN), four male Wistar rat groups were studied: (1) Control: vehicle; (2) Atorva: 3 mg/kg bw/day; (3) Carcinogen: BBN (0.05%); (4) Preventive Atorva: 3 mg/kg bw/day Atorva + BBN. A two phase protocol was used, in which the drug and the carcinogen were given between week 1 and 8 and tumor development or chemoprevention were expressed between week 9 and 20, when the bladders were collected for macroscopic, histological and immunohistochemical (p53, ki67, CD31) evaluation. Serum was assessed for markers of inflammation, proliferation and redox status. The incidence of bladder carcinoma was: control 0/8 (0%); Atorva 0/8 (0%); BBN 13/20 (65%) and Atorva + BBN 1/8 (12.5%). The number and volume of tumors were significantly lower in the Atorva + BBN group, with a marked reduction in hyperplasia, dysplasia and carcinoma in situ lesions. An anti-proliferative, anti-inflammatory and antioxidant profile was also observed in the preventive Atorva group. p53 and ki67 immunostaining were significantly increased in the BBN-treated rats, which was prevented in the Atorva + BBN group. No differences were found for CD31 expression. In conclusion, Atorvastatin had a clear inhibitory effect on bladder cancer development, probably due to its antioxidant, anti-proliferative and anti-inflammatory properties. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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11 pages, 186 KiB

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Clinical Relevance of CDH1 and CDH13 DNA-Methylation in Serum of Cervical Cancer Patients

by Abida Abudukadeer, Rania Bakry, Georg Goebel, Irene Mutz-Dehbalaie, Andreas Widschwendter, Günther K. Bonn and Heidi Fiegl

Int. J. Mol. Sci. 2012, 13(7), 8353-8363; https://doi.org/10.3390/ijms13078353 - 5 Jul 2012

Cited by 31 | Viewed by 8569

Abstract

This study was designed to investigate the DNA-methylation status of E-cadherin (CDH1) and H-cadherin (CDH13) in serum samples of cervical cancer patients and control patients with no malignant diseases and to evaluate the clinical utility of these [...] Read more.

This study was designed to investigate the DNA-methylation status of E-cadherin (CDH1) and H-cadherin (CDH13) in serum samples of cervical cancer patients and control patients with no malignant diseases and to evaluate the clinical utility of these markers. DNA-methylation status of CDH1 and CDH13 was analyzed by means of MethyLight-technology in serum samples from 49 cervical cancer patients and 40 patients with diseases other than cancer. To compare this methylation analysis with another technique, we analyzed the samples with a denaturing high performance liquid chromatography (DHPLC) PCR-method. The specificity and sensitivity of CDH1 DNA-methylation measured by MethyLight was 75% and 55%, and for CDH13 DNA-methylation 95% and 10%. We identified a specificity of 92.5% and a sensitivity of only 27% for the CDH1 DHPLC-PCR analysis. Multivariate analysis showed that serum CDH1 methylation-positive patients had a 7.8-fold risk for death (95% CI: 2.2–27.7; p = 0.001) and a 92.8-fold risk for relapse (95% CI: 3.9–2207.1; p = 0.005). We concluded that the serological detection of CDH1 and CDH13 DNA-hypermethylation is not an ideal diagnostic tool due to low diagnostic specificity and sensitivity. However, it was validated that CDH1 methylation analysis in serum samples may be of potential use as a prognostic marker for cervical cancer patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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14 pages, 389 KiB

Open AccessArticle

Genome-Wide Analysis of DNA Methylation and Expression of MicroRNAs in Breast Cancer Cells

by Sumiyo Morita, Ryou-u Takahashi, Riu Yamashita, Atsushi Toyoda, Takuro Horii, Mika Kimura, Asao Fujiyama, Kenta Nakai, Shoji Tajima, Ryo Matoba, Takahiro Ochiya and Izuho Hatada

Int. J. Mol. Sci. 2012, 13(7), 8259-8272; https://doi.org/10.3390/ijms13078259 - 3 Jul 2012

Cited by 38 | Viewed by 11014

Abstract

DNA methylation of promoters is linked to transcriptional silencing of protein-coding genes, and its alteration plays important roles in cancer formation. For example, hypermethylation of tumor suppressor genes has been seen in some cancers. Alteration of methylation in the promoters of microRNAs (miRNAs) [...] Read more.

DNA methylation of promoters is linked to transcriptional silencing of protein-coding genes, and its alteration plays important roles in cancer formation. For example, hypermethylation of tumor suppressor genes has been seen in some cancers. Alteration of methylation in the promoters of microRNAs (miRNAs) has also been linked to transcriptional changes in cancers; however, no systematic studies of methylation and transcription of miRNAs have been reported. In the present study, to clarify the relation between DNA methylation and transcription of miRNAs, next-generation sequencing and microarrays were used to analyze the methylation and expression of miRNAs, protein-coding genes, other non-coding RNAs (ncRNAs), and pseudogenes in the human breast cancer cell lines MCF7 and the adriamycin (ADR) resistant cell line MCF7/ADR. DNA methylation in the proximal promoter of miRNAs is tightly linked to transcriptional silencing, as it is with protein-coding genes. In protein-coding genes, highly expressed genes have CpG-rich proximal promoters whereas weakly expressed genes do not. This is only rarely observed in other gene categories, including miRNAs. The present study highlights the epigenetic similarities and differences between miRNA and protein-coding genes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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13 pages, 407 KiB

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Expression of Sox2 and Oct4 and Their Clinical Significance in Human Non-Small-Cell Lung Cancer

by Xinxin Li, Jinguang Wang, Zhiyun Xu, Aftab Ahmad, Encheng Li, Yuan Wang, Suli Qin and Qi Wang

Int. J. Mol. Sci. 2012, 13(6), 7663-7675; https://doi.org/10.3390/ijms13067663 - 21 Jun 2012

Cited by 93 | Viewed by 9993

Abstract

Sox2 and Oct4 are transcription factors with the characteristics of regulating self-renewal and differentiation of embryonic stem cell. The aim of this study was to detect the expression of Sox2 and Oct4 and analyze their clinical significance in human non-small-cell lung cancer (NSCLC). [...] Read more.

Sox2 and Oct4 are transcription factors with the characteristics of regulating self-renewal and differentiation of embryonic stem cell. The aim of this study was to detect the expression of Sox2 and Oct4 and analyze their clinical significance in human non-small-cell lung cancer (NSCLC). Expression of Sox2 and Oct4 were assayed in cancer tissues and their corresponding paracancerous tissues from 44 patients with NSCLC and 21 patients with benign tumors using immunohistochemistry, Western blot, reverse transcription polymerase chain reaction (RT-PCR). The correlation between the expression of Sox2 and Oct4 and tumor type, grade and prognosis and the utility of the two genes in discriminating between benign and malignant tumors were analyzed as well. The results showed that Sox2 and Oct4 positive staining was only seen in the nuclei of cancer cells but not in either the precancerous tissues or benign tumor tissues by immunohistochemistry (p < 0.01). Furthermore, in the lung cancer tissue, the positive rate for Sox2 and Oct4 was 70.5% and 54.5%, respectively. Meanwhile, clinicopathological correlations showed that the Oct4 expression level was significantly associated with poorer differentiation and higher TNM stage of the cancer (p < 0.05). Western blot and RT-PCR analysis showed similar results to immunohistochemistry. Follow-up analysis revealed that expression of Oct4 was significantly associated with poor prognosis of lung cancer. The conclusion is that Sox2 and Oct4 may act as the promising unit markers in directing NSCLC diagnosis and therapy. Also, Oct4 can be regarded as a novel predictor of poor prognosis for NSCLC patients undergoing resection. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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12 pages, 191 KiB

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O6-Methylguanine-Methyltransferase (MGMT) Promoter Methylation Status in Glioma Stem-Like Cells is Correlated to Temozolomide Sensitivity Under Differentiation-Promoting Conditions

by Claire Villalva, Ulrich Cortes, Michel Wager, Jean-Marc Tourani, Pierre Rivet, Celine Marquant, Sebastien Martin, Ali G. Turhan and Lucie Karayan-Tapon

Int. J. Mol. Sci. 2012, 13(6), 6983-6994; https://doi.org/10.3390/ijms13066983 - 7 Jun 2012

Cited by 45 | Viewed by 8617

Abstract

Glioblastoma (GBM) is the most malignant type of primary brain tumor with a very poor prognosis. The actual standard protocol of treatment for GBM patients consists of radiotherapy and concomitant temozolomide (TMZ). However, the therapeutic efficacy of this treatment is limited due to [...] Read more.

Glioblastoma (GBM) is the most malignant type of primary brain tumor with a very poor prognosis. The actual standard protocol of treatment for GBM patients consists of radiotherapy and concomitant temozolomide (TMZ). However, the therapeutic efficacy of this treatment is limited due to tumor recurrence and TMZ resistance. Recently isolated, glioma stem-like cells (GSCs) are thought to represent the population of tumorigenic cells responsible for GBM resistance and recurrence following surgery and chemotherapy. In addition, MGMT (O6-methylguanine-methyltransferase) methylation is considered as one of the principal mechanisms contributing to TMZ sensitivity of GBM. In this study we have isolated GSCs from 10 adult GBM patients and investigated the relationship between MGMT methylation status and Temozolomide (TMZ) sensitivity of these lines grown either in stem-like or differentiation promoting conditions. Sensitivity to TMZ was significantly associated with MGMT methylation status in cells committed to differentiation but not in stem-like cells. In addition, patients harboring highly methylated MGMT promoters had a longer overall survival. These results reveal the importance of the differentiation process when considering the predictive value of MGMT status in GSCs for clinical response to TMZ. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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14 pages, 385 KiB

Open AccessArticle

Role of Helicity on the Anticancer Mechanism of Action of Cationic-Helical Peptides

by Yi-Bing Huang, Li-Yan He, Hong-Yu Jiang and Yu-Xin Chen

Int. J. Mol. Sci. 2012, 13(6), 6849-6862; https://doi.org/10.3390/ijms13066849 - 5 Jun 2012

Cited by 51 | Viewed by 8173

Abstract

In the present study, the 26-residue amphipathic α-helical peptide A12L/A20L (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide) with strong anticancer activity and specificity was used as the framework to study the effects of helicity of α-helical anticancer peptides on biological activities. Helicity was systematically modulated by introducing D-amino acids [...] Read more.

In the present study, the 26-residue amphipathic α-helical peptide A12L/A20L (Ac-KWKSFLKTFKSLKKTVLHTLLKAISS-amide) with strong anticancer activity and specificity was used as the framework to study the effects of helicity of α-helical anticancer peptides on biological activities. Helicity was systematically modulated by introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix. Peptide helicity was measured by circular dichroism spectroscopy and was demonstrated to correlate with peptide hydrophobicity and the number of D-amino acid substitutions. Biological studies showed that strong hemolytic activity of peptides generally correlated with high hydrophobicity and helicity. Lower helicity caused the decrease of anti-HeLa activity of peptides. By introducing D-amino acids to replace the original L-amino acids on the non-polar face or the polar face of the helix, we improved the therapeutic index of A12L/A20L against HeLa cells by 9-fold and 22-fold, respectively. These results show that the helicity of anticancer peptides plays a crucial role for biological activities. This specific rational approach of peptide design could be a powerful method to improve the specificity of anticancer peptides as promising therapeutics in clinical practices. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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8 pages, 399 KiB

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CD146 Expression Correlates with Epithelial-Mesenchymal Transition Markers and a Poor Prognosis in Gastric Cancer

by Wen-Fang Liu, Shu-Rong Ji, Jian-Jun Sun, Yi Zhang, Zhong-Yan Liu, Ai-Bin Liang and Hua-Zong Zeng

Int. J. Mol. Sci. 2012, 13(5), 6399-6406; https://doi.org/10.3390/ijms13056399 - 23 May 2012

Cited by 72 | Viewed by 8725

Abstract

CD146 has been regarded as a novel potential therapeutic target for multiple cancers. The aim of the study was to investigate the expression of CD146 in gastric cancer and evaluate its clinical-pathological and prognostic significance. The expression of CD146 and three epithelial-mesenchymal transition [...] Read more.

CD146 has been regarded as a novel potential therapeutic target for multiple cancers. The aim of the study was to investigate the expression of CD146 in gastric cancer and evaluate its clinical-pathological and prognostic significance. The expression of CD146 and three epithelial-mesenchymal transition (EMT)-related proteins (E-cadherin, β-catenin and vimentin) was examined in 144 gastric cancers by immunohistochemistry. Fifty-nine cases (41.0%) were defined as positive for CD146 expression. We found that CD146 expression correlated positively with lymph node involvement and a poor prognosis, and retained an independent prognostic factor for gastric cancer patients. Furthermore, positive expression of CD146 was strongly associated with loss of the epithelial marker E-cadherin and acquisition of the expression of the mesenchymal markers nuclear β-catenin and vimentin. These findings suggest that CD146 might promote EMT and progression in gastric cancer, and thus may be a potential therapeutic target for patients with gastric cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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18 pages, 785 KiB

Open AccessArticle

Revealing the Anti-Tumor Effect of Artificial miRNA p-27-5p on Human Breast Carcinoma Cell Line T-47D

by Chien-Wei Tseng, Hsuan-Cheng Huang, Arthur Chun-Chieh Shih, Ya-Ya Chang, Chung-Cheng Hsu, Jen-Yun Chang, Wen-Hsiung Li and Hsueh-Fen Juan

Int. J. Mol. Sci. 2012, 13(5), 6352-6369; https://doi.org/10.3390/ijms13056352 - 23 May 2012

Cited by 5 | Viewed by 9788

Abstract

microRNAs (miRNAs) cause mRNA degradation or translation suppression of their target genes. Previous studies have found direct involvement of miRNAs in cancer initiation and progression. Artificial miRNAs, designed to target single or multiple genes of interest, provide a new therapeutic strategy for cancer. [...] Read more.

microRNAs (miRNAs) cause mRNA degradation or translation suppression of their target genes. Previous studies have found direct involvement of miRNAs in cancer initiation and progression. Artificial miRNAs, designed to target single or multiple genes of interest, provide a new therapeutic strategy for cancer. This study investigates the anti-tumor effect of a novel artificial miRNA, miR P-27-5p, on breast cancer. In this study, we reveal that miR P-27-5p downregulates the differential gene expressions associated with the protein modification process and regulation of cell cycle in T-47D cells. Introduction of this novel artificial miRNA, miR P-27-5p, into breast cell lines inhibits cell proliferation and induces the first “gap” phase (G1) cell cycle arrest in cancer cell lines but does not affect normal breast cells. We further show that miR P-27-5p targets the 3′-untranslated mRNA region (3′-UTR) of cyclin-dependent kinase 4 (CDK4) and reduces both the mRNA and protein level of CDK4, which in turn, interferes with phosphorylation of the retinoblastoma protein (RB1). Overall, our data suggest that the effects of miR p-27-5p on cell proliferation and G1 cell cycle arrest are through the downregulation of CDK4 and the suppression of RB1 phosphorylation. This study opens avenues for future therapies targeting breast cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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16 pages, 394 KiB

Open AccessArticle

Characterization of ARF-BP1/HUWE1 Interactions with CTCF, MYC, ARF and p53 in MYC-Driven B Cell Neoplasms

by Chen-Feng Qi, Yong-Soo Kim, Shao Xiang, Ziedulla Abdullaev, Ted A. Torrey, Siegfried Janz, Alexander L. Kovalchuk, Jiafang Sun, Delin Chen, William C. Cho, Wei Gu and Herbert C. Morse III

Int. J. Mol. Sci. 2012, 13(5), 6204-6219; https://doi.org/10.3390/ijms13056204 - 21 May 2012

Cited by 29 | Viewed by 9967

Abstract

Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both [...] Read more.

Transcriptional activation of MYC is a hallmark of many B cell lineage neoplasms. MYC provides a constitutive proliferative signal but can also initiate ARF-dependent activation of p53 and apoptosis. The E3 ubiquitin ligase, ARF-BP1, encoded by HUWE1, modulates the activity of both the MYC and the ARF-p53 signaling pathways, prompting us to determine if it is involved in the pathogenesis of MYC-driven B cell lymphomas. ARF-BP1 was expressed at high levels in cell lines from lymphomas with either wild type or mutated p53 but not in ARF-deficient cells. Downregulation of ARF-BP1 resulted in elevated steady state levels of p53, growth arrest and apoptosis. Co-immunoprecipitation studies identified a multiprotein complex comprised of ARF-BP1, ARF, p53, MYC and the multifunctional DNA-binding factor, CTCF, which is involved in the transcriptional regulation of MYC, p53 and ARF. ARF-BP1 bound and ubiquitylated CTCF leading to its proteasomal degradation. ARF-BP1 and CTCF thus appear to be key cofactors linking the MYC proliferative and p53-ARF apoptotic pathways. In addition, ARF-BP1 could be a therapeutic target for MYC-driven B lineage neoplasms, even if p53 is inactive, with inhibition reducing the transcriptional activity of MYC for its target genes and stabilizing the apoptosis-promoting activities of p53. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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9 pages, 195 KiB

Open AccessArticle

Evaluation of HER2 Gene Amplification in Breast Cancer Using Nuclei Microarray in Situ Hybridization

by Huiyong Jiang, Xiaoyan Bai, Cheng Zhang and Xuefeng Zhang

Int. J. Mol. Sci. 2012, 13(5), 5519-5527; https://doi.org/10.3390/ijms13055519 - 8 May 2012

Cited by 6 | Viewed by 11403

Abstract

Fluorescence in situ hybridization (FISH) assay is considered the “gold standard” in evaluating HER2/neu (HER2) gene status. However, FISH detection is costly and time consuming. Thus, we established nuclei microarray with extracted intact nuclei from paraffin embedded breast cancer tissues for FISH detection. [...] Read more.

Fluorescence in situ hybridization (FISH) assay is considered the “gold standard” in evaluating HER2/neu (HER2) gene status. However, FISH detection is costly and time consuming. Thus, we established nuclei microarray with extracted intact nuclei from paraffin embedded breast cancer tissues for FISH detection. The nuclei microarray FISH (NMFISH) technology serves as a useful platform for analyzing HER2 gene/chromosome 17 centromere ratio. We examined HER2 gene status in 152 cases of invasive ductal carcinomas of the breast that were resected surgically with FISH and NMFISH. HER2 gene amplification status was classified according to the guidelines of the American Society of Clinical Oncology and College of American Pathologists (ASCO/CAP). Comparison of the cut-off values for HER2/chromosome 17 centromere copy number ratio obtained by NMFISH and FISH showed that there was almost perfect agreement between the two methods (κ coefficient 0.920). The results of the two methods were almost consistent for the evaluation of HER2 gene counts. The present study proved that NMFISH is comparable with FISH for evaluating HER2 gene status. The use of nuclei microarray technology is highly efficient, time and reagent conserving and inexpensive. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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21 pages, 358 KiB

Open AccessArticle

Evaluation of the Adenocarcinoma-Associated Gene AGR2 and the Intestinal Stem Cell Marker LGR5 as Biomarkers in Colorectal Cancer

by Manuel Valladares-Ayerbes, Moisés Blanco-Calvo, Margarita Reboredo, María J. Lorenzo-Patiño, Pilar Iglesias-Díaz, Mar Haz, Silvia Díaz-Prado, Vanessa Medina, Isabel Santamarina, Sonia Pértega, Angélica Figueroa and Luis M. Antón-Aparicio

Int. J. Mol. Sci. 2012, 13(4), 4367-4387; https://doi.org/10.3390/ijms13044367 - 5 Apr 2012

Cited by 44 | Viewed by 10317

Abstract

We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used [...] Read more.

We aim to estimate the diagnostic performances of anterior gradient homolog-2 (AGR2) and Leucine-rich repeat-containing-G-protein-coupled receptor 5 (LGR5) in peripheral blood (PB) as mRNA biomarkers in colorectal cancer (CRC) and to explore their prognostic significance. Real-time PCR was used to analyze AGR2 and LGR5 in 54 stages I-IV CRC patients and 19 controls. Both mRNAs were significantly increased in PB from CRC patients compared to controls. The area under the receiver-operating characteristic curves were 0.722 (p = 0.006), 0.376 (p = 0.123) and 0.767 (p = 0.001) for AGR2, LGR5 and combined AGR2/LGR5, respectively. The AGR2/LGR5 assay resulted in 67.4% sensitivity and 94.7% specificity. AGR2 correlated with pT3–pT4 and high-grade tumors. LGR5 correlated with metastasis, R2 resections and high-grade. The progression-free survival (PFS) of patients with high AGR2 was reduced (p = 0.037; HR, 2.32), also in the stage I-III subgroup (p = 0.046). LGR5 indicated a poor prognosis regarding both PFS (p = 0.007; HR, 1.013) and overall survival (p = 0.045; HR, 1.01). High AGR2/LGR5 was associated with poor PFS (p = 0.014; HR, 2.8) by multivariate analysis. Our findings indicate that the assessment of AGR2 and LGR5 in PB might reflect the presence of circulating tumor cells (CTC) and stem cell like CTC in CRC. Increased AGR2 and LGR5 are associated with poor outcomes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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Review

Jump to: Research

20 pages, 2277 KiB

Open AccessReview

Anaplastic Lymphoma Kinase (ALK) Receptor Tyrosine Kinase: A Catalytic Receptor with Many Faces

by Hao Huang

Int. J. Mol. Sci. 2018, 19(11), 3448; https://doi.org/10.3390/ijms19113448 - 2 Nov 2018

Cited by 55 | Viewed by 9560

Abstract

The anaplastic lymphoma kinase (ALK) receptor is a membrane-bound tyrosine kinase. The pathogenesis of several cancers is closely related to aberrant forms of ALK or aberrant ALK expression, including ALK fusion proteins, ALK-activated point mutations, and ALK amplification. Clinical applications of different ALK [...] Read more.

The anaplastic lymphoma kinase (ALK) receptor is a membrane-bound tyrosine kinase. The pathogenesis of several cancers is closely related to aberrant forms of ALK or aberrant ALK expression, including ALK fusion proteins, ALK-activated point mutations, and ALK amplification. Clinical applications of different ALK inhibitors represent significant progress in targeted therapy. Knowledge of different aspects of ALK biology can provide significant information to further the understanding of this receptor tyrosine kinase. In this mini-review, we briefly summarize different features of ALK. We also summarize some recent research advances on ALK fusion proteins in cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 680 KiB

Open AccessReview

Renal Cell Tumors: Understanding Their Molecular Pathological Epidemiology and the 2016 WHO Classification

by Kentaro Inamura

Int. J. Mol. Sci. 2017, 18(10), 2195; https://doi.org/10.3390/ijms18102195 - 20 Oct 2017

Cited by 127 | Viewed by 9549

Abstract

Accumulating evidence suggests that renal cell tumors represent a group of histologically and molecularly heterogeneous diseases, even within the same histological subtype. In accordance with the increased understanding of the morphological, immunohistochemical, molecular, and epidemiological characteristics of renal cell tumors, the World Health [...] Read more.

Accumulating evidence suggests that renal cell tumors represent a group of histologically and molecularly heterogeneous diseases, even within the same histological subtype. In accordance with the increased understanding of the morphological, immunohistochemical, molecular, and epidemiological characteristics of renal cell tumors, the World Health Organization (WHO) classification of renal cell tumors has been modified. This review provides perspectives on both new and current subtypes of renal cell tumors, as well as on the emerging/provisional renal cell carcinomas in the new 2016 WHO classification, which focuses on features of their molecular pathological epidemiology. The WHO classification will require additional revisions to enable the classification of renal cell tumors as clinically meaningful subtypes and provide a better understanding of the unique characteristics of renal cell tumors. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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14 pages, 537 KiB

Open AccessReview

Erythropoietin and Its Angiogenic Activity

by Patrícia Kimáková, Peter Solár, Zuzana Solárová, Radovan Komel and Nataša Debeljak

Int. J. Mol. Sci. 2017, 18(7), 1519; https://doi.org/10.3390/ijms18071519 - 13 Jul 2017

Cited by 92 | Viewed by 6969

Abstract

Erythropoietin (EPO) is the main hematopoietic hormone acting on progenitor red blood cells via stimulation of cell growth, differentiation, and anti-apoptosis. However, its receptor (EPOR) is also expressed in various non-hematopoietic tissues, including endothelium. EPO is a pleiotropic growth factor that exhibits growth [...] Read more.

Erythropoietin (EPO) is the main hematopoietic hormone acting on progenitor red blood cells via stimulation of cell growth, differentiation, and anti-apoptosis. However, its receptor (EPOR) is also expressed in various non-hematopoietic tissues, including endothelium. EPO is a pleiotropic growth factor that exhibits growth stimulation and cell/tissue protection on numerous cells and tissues. In this article we review the angiogenesis potential of EPO on endothelial cells in heart, brain, and leg ischemia, as well as its role in retinopathy protection and tumor promotion. Furthermore, the effect of EPO on bone marrow and adipose tissue is also discussed. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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16 pages, 1025 KiB

Open AccessReview

Target Therapies for Uterine Carcinosarcomas: Current Evidence and Future Perspectives

by Salvatore Giovanni Vitale, Antonio Simone Laganà, Stella Capriglione, Roberto Angioli, Valentina Lucia La Rosa, Salvatore Lopez, Gaetano Valenti, Fabrizio Sapia, Giuseppe Sarpietro, Salvatore Butticè, Carmelo Tuscano, Daniele Fanale, Alessandro Tropea and Diego Rossetti

Int. J. Mol. Sci. 2017, 18(5), 1100; https://doi.org/10.3390/ijms18051100 - 20 May 2017

Cited by 36 | Viewed by 8523

Abstract

Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due [...] Read more.

Carcinosarcomas (CS) in gynecology are very infrequent and represent only 2–5% of uterine cancers. Despite surgical cytoreduction and subsequent chemotherapy being the primary treatment for uterine CS, the overall five-year survival rate is 30 ± 9% and recurrence is extremely common (50–80%). Due to the poor prognosis of CS, new strategies have been developed in the last few decades, targeting known dysfunctional molecular pathways for immunotherapy. In this paper, we aimed to gather the available evidence on the latest therapies for the treatment of CS. We performed a systematic review using the terms “uterine carcinosarcoma”, “uterine Malignant Mixed Müllerian Tumors”, “target therapies”, “angiogenesis therapy”, “cancer stem cell therapy”, “prognostic biomarker”, and “novel antibody-drug”. Based on our results, the differential expression and accessibility of epithelial cell adhesion molecule-1 on metastatic/chemotherapy-resistant CS cells in comparison to normal tissues and Human Epidermal Growth Factor Receptor 2 (HER2) open up new possibilities in the field of target therapy. Nevertheless, future investigations are needed to clarify the impact of these new therapies on survival rate and medium-/long-term outcomes. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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24 pages, 1478 KiB

Open AccessReview

Role of Autophagy and Apoptosis in Non-Small-Cell Lung Cancer

by Guangbo Liu, Fen Pei, Fengqing Yang, Lingxiao Li, Amit Dipak Amin, Songnian Liu, J. Ross Buchan and William C. Cho

Int. J. Mol. Sci. 2017, 18(2), 367; https://doi.org/10.3390/ijms18020367 - 10 Feb 2017

Cited by 356 | Viewed by 21578

Abstract

Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, [...] Read more.

Non-small-cell lung cancer (NSCLC) constitutes 85% of all lung cancers, and is the leading cause of cancer-related death worldwide. The poor prognosis and resistance to both radiation and chemotherapy warrant further investigation into the molecular mechanisms of NSCLC and the development of new, more efficacious therapeutics. The processes of autophagy and apoptosis, which induce degradation of proteins and organelles or cell death upon cellular stress, are crucial in the pathophysiology of NSCLC. The close interplay between autophagy and apoptosis through shared signaling pathways complicates our understanding of how NSCLC pathophysiology is regulated. The apoptotic effect of autophagy is controversial as both inhibitory and stimulatory effects have been reported in NSCLC. In addition, crosstalk of proteins regulating both autophagy and apoptosis exists. Here, we review the recent advances of the relationship between autophagy and apoptosis in NSCLC, aiming to provide few insights into the discovery of novel pathogenic factors and the development of new cancer therapeutics. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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14 pages, 1773 KiB

Open AccessReview

MicroRNAs, DNA Damage Response, and Cancer Treatment

by Mingyang He, Weiwei Zhou, Chuang Li and Mingxiong Guo

Int. J. Mol. Sci. 2016, 17(12), 2087; https://doi.org/10.3390/ijms17122087 - 12 Dec 2016

Cited by 49 | Viewed by 7904

Abstract

As a result of various stresses, lesions caused by DNA-damaging agents occur constantly in each cell of the human body. Generally, DNA damage is recognized and repaired by the DNA damage response (DDR) machinery, and the cells survive. When repair fails, the genomic [...] Read more.

As a result of various stresses, lesions caused by DNA-damaging agents occur constantly in each cell of the human body. Generally, DNA damage is recognized and repaired by the DNA damage response (DDR) machinery, and the cells survive. When repair fails, the genomic integrity of the cell is disrupted—a hallmark of cancer. In addition, the DDR plays a dual role in cancer development and therapy. Cancer radiotherapy and chemotherapy are designed to eliminate cancer cells by inducing DNA damage, which in turn can promote tumorigenesis. Over the past two decades, an increasing number of microRNAs (miRNAs), small noncoding RNAs, have been identified as participating in the processes regulating tumorigenesis and responses to cancer treatment with radiation therapy or genotoxic chemotherapies, by modulating the DDR. The purpose of this review is to summarize the recent findings on how miRNAs regulate the DDR and discuss the therapeutic functions of miRNAs in cancer in the context of DDR regulation. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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24 pages, 1484 KiB

Open AccessReview

The Bromodomain and Extra-Terminal Domain (BET) Family: Functional Anatomy of BET Paralogous Proteins

by Yasushi Taniguchi

Int. J. Mol. Sci. 2016, 17(11), 1849; https://doi.org/10.3390/ijms17111849 - 7 Nov 2016

Cited by 251 | Viewed by 18702

Abstract

The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have [...] Read more.

The Bromodomain and Extra-Terminal Domain (BET) family of proteins is characterized by the presence of two tandem bromodomains and an extra-terminal domain. The mammalian BET family of proteins comprises BRD2, BRD3, BRD4, and BRDT, which are encoded by paralogous genes that may have been generated by repeated duplication of an ancestral gene during evolution. Bromodomains that can specifically bind acetylated lysine residues in histones serve as chromatin-targeting modules that decipher the histone acetylation code. BET proteins play a crucial role in regulating gene transcription through epigenetic interactions between bromodomains and acetylated histones during cellular proliferation and differentiation processes. On the other hand, BET proteins have been reported to mediate latent viral infection in host cells and be involved in oncogenesis. Human BRD4 is involved in multiple processes of the DNA virus life cycle, including viral replication, genome maintenance, and gene transcription through interaction with viral proteins. Aberrant BRD4 expression contributes to carcinogenesis by mediating hyperacetylation of the chromatin containing the cell proliferation-promoting genes. BET bromodomain blockade using small-molecule inhibitors gives rise to selective repression of the transcriptional network driven by c-MYC These inhibitors are expected to be potential therapeutic drugs for a wide range of cancers. This review presents an overview of the basic roles of BET proteins and highlights the pathological functions of BET and the recent developments in cancer therapy targeting BET proteins in animal models. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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23 pages, 1077 KiB

Open AccessReview

Targeted Cancer Therapy: Vital Oncogenes and a New Molecular Genetic Paradigm for Cancer Initiation Progression and Treatment

by Rudolph E. Willis

Int. J. Mol. Sci. 2016, 17(9), 1552; https://doi.org/10.3390/ijms17091552 - 14 Sep 2016

Cited by 26 | Viewed by 11278

Abstract

It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during [...] Read more.

It has been declared repeatedly that cancer is a result of molecular genetic abnormalities. However, there has been no working model describing the specific functional consequences of the deranged genomic processes that result in the initiation and propagation of the cancer process during carcinogenesis. We no longer need to question whether or not cancer arises as a result of a molecular genetic defect within the cancer cell. The legitimate questions are: how and why? This article reviews the preeminent data on cancer molecular genetics and subsequently proposes that the sentinel event in cancer initiation is the aberrant production of fused transcription activators with new molecular properties within normal tissue stem cells. This results in the production of vital oncogenes with dysfunctional gene activation transcription properties, which leads to dysfunctional gene regulation, the aberrant activation of transduction pathways, chromosomal breakage, activation of driver oncogenes, reactivation of stem cell transduction pathways and the activation of genes that result in the hallmarks of cancer. Furthermore, a novel holistic molecular genetic model of cancer initiation and progression is presented along with a new paradigm for the approach to personalized targeted cancer therapy, clinical monitoring and cancer diagnosis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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25 pages, 894 KiB

Open AccessReview

Importance of Estrogenic Signaling and Its Mediated Receptors in Prostate Cancer

by Kin-Mang Lau and Ka-Fai To

Int. J. Mol. Sci. 2016, 17(9), 1434; https://doi.org/10.3390/ijms17091434 - 31 Aug 2016

Cited by 35 | Viewed by 7871

Abstract

Prostate cancer (PCa) treatment was first established by Huggins and Hodges in 1941, primarily described as androgen deprivation via interference of testicular androgen production. The disease remains incurable with relapse of hormone-refractory cancer after treatments. Epidemiological and clinical studies disclosed the importance of [...] Read more.

Prostate cancer (PCa) treatment was first established by Huggins and Hodges in 1941, primarily described as androgen deprivation via interference of testicular androgen production. The disease remains incurable with relapse of hormone-refractory cancer after treatments. Epidemiological and clinical studies disclosed the importance of estrogens in PCa. Discovery of estrogen receptor ERβ prompted direct estrogenic actions, in conjunction with ERα, on PCa cells. Mechanistically, ERs upon ligand binding transactivate target genes at consensus genomic sites via interactions with various transcriptional co-regulators to mold estrogenic signaling. With animal models, Noble revealed estrogen dependencies of PCa, providing insight into potential uses of antiestrogens in the treatment. Subsequently, various clinical trials were conducted and molecular and functional consequences of antiestrogen treatment in PCa were delineated. Besides, estrogens can also trigger rapid non-genomic signaling responses initiated at the plasma membrane, at least partially via an orphan G-protein-coupled receptor GPR30. Activation of GPR30 significantly inhibited in vitro and in vivo PCa cell growth and the underlying mechanism was elucidated. Currently, molecular networks of estrogenic and antiestrogenic signaling via ERα, ERβ and GPR30 in PCa have not been fully deciphered. This crucial information could be beneficial to further developments of effective estrogen- and antiestrogen-based therapy for PCa patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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31 pages, 2850 KiB

Open AccessReview

Tamoxifen Resistance: Emerging Molecular Targets

by Milena Rondón-Lagos, Victoria E. Villegas, Nelson Rangel, Magda Carolina Sánchez and Peter G. Zaphiropoulos

Int. J. Mol. Sci. 2016, 17(8), 1357; https://doi.org/10.3390/ijms17081357 - 19 Aug 2016

Cited by 109 | Viewed by 16745

Abstract

17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast [...] Read more.

17β-Estradiol (E2) plays a pivotal role in the development and progression of breast cancer. As a result, blockade of the E2 signal through either tamoxifen (TAM) or aromatase inhibitors is an important therapeutic strategy to treat or prevent estrogen receptor (ER) positive breast cancer. However, resistance to TAM is the major obstacle in endocrine therapy. This resistance occurs either de novo or is acquired after an initial beneficial response. The underlying mechanisms for TAM resistance are probably multifactorial and remain largely unknown. Considering that breast cancer is a very heterogeneous disease and patients respond differently to treatment, the molecular analysis of TAM’s biological activity could provide the necessary framework to understand the complex effects of this drug in target cells. Moreover, this could explain, at least in part, the development of resistance and indicate an optimal therapeutic option. This review highlights the implications of TAM in breast cancer as well as the role of receptors/signal pathways recently suggested to be involved in the development of TAM resistance. G protein—coupled estrogen receptor, Androgen Receptor and Hedgehog signaling pathways are emerging as novel therapeutic targets and prognostic indicators for breast cancer, based on their ability to mediate estrogenic signaling in ERα-positive or -negative breast cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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25 pages, 1842 KiB

Open AccessReview

The Role of α1-Adrenoceptor Antagonists in the Treatment of Prostate and Other Cancers

by Mallory Batty, Rachel Pugh, Ilampirai Rathinam, Joshua Simmonds, Edwin Walker, Amanda Forbes, Shailendra Anoopkumar-Dukie, Catherine M. McDermott, Briohny Spencer, David Christie and Russ Chess-Williams

Int. J. Mol. Sci. 2016, 17(8), 1339; https://doi.org/10.3390/ijms17081339 - 16 Aug 2016

Cited by 30 | Viewed by 9110

Abstract

This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease [...] Read more.

This review evaluates the role of α-adrenoceptor antagonists as a potential treatment of prostate cancer (PCa). Cochrane, Google Scholar and Pubmed were accessed to retrieve sixty-two articles for analysis. In vitro studies demonstrate that doxazosin, prazosin and terazosin (quinazoline α-antagonists) induce apoptosis, decrease cell growth, and proliferation in PC-3, LNCaP and DU-145 cell lines. Similarly, the piperazine based naftopidil induced cell cycle arrest and death in LNCaP-E9 cell lines. In contrast, sulphonamide based tamsulosin did not exhibit these effects. In vivo data was consistent with in vitro findings as the quinazoline based α-antagonists prevented angiogenesis and decreased tumour mass in mice models of PCa. Mechanistically the cytotoxic and antitumor effects of the α-antagonists appear largely independent of α 1-blockade. The proposed targets include: VEGF, EGFR, HER2/Neu, caspase 8/3, topoisomerase 1 and other mitochondrial apoptotic inducing factors. These cytotoxic effects could not be evaluated in human studies as prospective trial data is lacking. However, retrospective studies show a decreased incidence of PCa in males exposed to α-antagonists. As human data evaluating the use of α-antagonists as treatments are lacking; well designed, prospective clinical trials are needed to conclusively demonstrate the anticancer properties of quinazoline based α-antagonists in PCa and other cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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22 pages, 903 KiB

Open AccessReview

A Mini-Review for Cancer Immunotherapy: Molecular Understanding of PD-1/PD-L1 Pathway & Translational Blockade of Immune Checkpoints

by Yongshu Li, Fangfei Li, Feng Jiang, Xiaoqing Lv, Rongjiang Zhang, Aiping Lu and Ge Zhang

Int. J. Mol. Sci. 2016, 17(7), 1151; https://doi.org/10.3390/ijms17071151 - 18 Jul 2016

Cited by 134 | Viewed by 16446

Abstract

Interference of the binding of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has become a new inspiring immunotherapy for resisting cancers. To date, the FDA has approved two PD-1 monoclonal antibody drugs against cancer as well as a monoclonal [...] Read more.

Interference of the binding of programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) has become a new inspiring immunotherapy for resisting cancers. To date, the FDA has approved two PD-1 monoclonal antibody drugs against cancer as well as a monoclonal antibody for PD-L1. More PD-1 and PD-L1 monoclonal antibody drugs are on their way in clinical trials. In this review, we focused on the mechanism of the PD-1/PD-L1 signaling pathway and the monoclonal antibodies (mAbs) against PD-1 and PD-L1, which were approved by the FDA or are still in clinical trials. And also presented is the prospect of the PD-1/PD-L1 immune checkpoint blockade in the next generation of immunotherapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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20 pages, 1359 KiB

Open AccessReview

Bladder Cancer Stem-Like Cells: Their Origin and Therapeutic Perspectives

by Tomokazu Ohishi, Fumitaka Koga and Toshiro Migita

Int. J. Mol. Sci. 2016, 17(1), 43; https://doi.org/10.3390/ijms17010043 - 29 Dec 2015

Cited by 43 | Viewed by 8743

Abstract

Bladder cancer (BC), the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients [...] Read more.

Bladder cancer (BC), the most common cancer arising from the human urinary tract, consists of two major clinicopathological phenotypes: muscle-invasive bladder cancer (MIBC) and non-muscle-invasive bladder cancer (NMIBC). MIBC frequently metastasizes and is associated with an unfavorable prognosis. A certain proportion of patients with metastatic BC can achieve a remission with systemic chemotherapy; however, the disease relapses in most cases. Evidence suggests that MIBC comprises a small population of cancer stem cells (CSCs), which may be resistant to these treatments and may be able to form new tumors in the bladder or other organs. Therefore, the unambiguous identification of bladder CSCs and the development of targeted therapies are urgently needed. Nevertheless, it remains unclear where bladder CSCs originate and how they are generated. We review recent studies on bladder CSCs, specifically focusing on their proposed origin and the possible therapeutic options based on the CSC theory. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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19 pages, 699 KiB

Open AccessReview

Mesenchymal Stem Cell-Mediated Effects of Tumor Support or Suppression

by Ki-Jong Rhee, Jong In Lee and Young Woo Eom

Int. J. Mol. Sci. 2015, 16(12), 30015-30033; https://doi.org/10.3390/ijms161226215 - 16 Dec 2015

Cited by 176 | Viewed by 10921

Abstract

Mesenchymal stem cells (MSCs) can exhibit a marked tropism towards site of tumors. Many studies have reported that tumor progression and metastasis increase by MSCs. In contrast, other studies have shown that MSCs suppress growth of tumors. MSCs contribute to tumor growth promotion [...] Read more.

Mesenchymal stem cells (MSCs) can exhibit a marked tropism towards site of tumors. Many studies have reported that tumor progression and metastasis increase by MSCs. In contrast, other studies have shown that MSCs suppress growth of tumors. MSCs contribute to tumor growth promotion by several mechanisms: (1) transition to tumor-associated fibroblasts; (2) suppression of immune response; (3) promotion of angiogenesis; (4) stimulation of epithelial-mesenchymal transition (EMT); (5) contribution to the tumor microenvironment; (6) inhibition of tumor cell apoptosis; and (7) promotion of tumor metastasis. In contrast to the tumor-promoting properties, MSCs inhibit tumor growth by increasing inflammatory infiltration, inhibiting angiogenesis, suppressing Wnt signaling and AKT signaling, and inducing cell cycle arrest and apoptosis. In this review, we will discuss potential mechanisms by which MSC mediates tumor support or suppression and then the possible tumor-specific therapeutic strategies using MSCs as delivery vehicles, based on their homing potential to tumors. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 1462 KiB

Open AccessReview

DNA Repair—A Double-Edged Sword in the Genomic Stability of Cancer Cells—The Case of Chronic Myeloid Leukemia

by Elzbieta Pawlowska and Janusz Blasiak

Int. J. Mol. Sci. 2015, 16(11), 27535-27549; https://doi.org/10.3390/ijms161126049 - 18 Nov 2015

Cited by 26 | Viewed by 9550

Abstract

Genomic instability is a common feature of cancer cells, which can result from aberrant DNA damage reaction (DDR). We and others showed that the well-known BCR-ABL1 fusion oncogene, the cause of chronic myeloid leukemia, induced an increased production of reactive oxygen species (ROS) [...] Read more.

Genomic instability is a common feature of cancer cells, which can result from aberrant DNA damage reaction (DDR). We and others showed that the well-known BCR-ABL1 fusion oncogene, the cause of chronic myeloid leukemia, induced an increased production of reactive oxygen species (ROS) and conferred therapeutic drug resistance by suppression of apoptotic signaling, prolonged G2/M arrest and stimulation of several pathways of DNA repair. However, to protect from apoptosis, cancer cells may tolerate some DNA lesions, which may increase genomic instability. Moreover, BCR/ABL1-stimulated DNA repair might be faulty, especially non-homologous end joining in its alternative forms. Normal DNA repair can remove DNA damage and prevent mutations, reducing genome instability, but on the other hand, due to its imprecise nature, it may increase genomic instability by increasing the ratio of mutagenic DNA lesions. The example of BCR-ABL1-expressing cells shows that DNA repair can both increase and decrease genomic instability of cancer cells and understanding the mechanism of the regulation of these opposite effects would be helpful in anticancer strategies. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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26 pages, 3655 KiB

Open AccessReview

EZH2 in Bladder Cancer, a Promising Therapeutic Target

by Mónica Martínez-Fernández, Carolina Rubio, Cristina Segovia, Fernando F. López-Calderón, Marta Dueñas and Jesús M. Paramio

Int. J. Mol. Sci. 2015, 16(11), 27107-27132; https://doi.org/10.3390/ijms161126000 - 13 Nov 2015

Cited by 61 | Viewed by 11429

Abstract

Bladder Cancer (BC) represents a current clinical and social challenge. The recent studies aimed to describe the genomic landscape of BC have underscored the relevance of epigenetic alterations in the pathogenesis of these tumors. Among the epigenetic alterations, histone modifications occupied a central [...] Read more.

Bladder Cancer (BC) represents a current clinical and social challenge. The recent studies aimed to describe the genomic landscape of BC have underscored the relevance of epigenetic alterations in the pathogenesis of these tumors. Among the epigenetic alterations, histone modifications occupied a central role not only in cancer, but also in normal organism homeostasis and development. EZH2 (Enhancer of Zeste Homolog 2) belongs to the Polycomb repressive complex 2 as its catalytic subunit, which through the trimethylation of H3 (Histone 3) on K27 (Lysine 27), produces gene silencing. EZH2 is frequently overexpressed in multiple tumor types, including BC, and plays multiple roles besides the well-recognized histone mark generation. In this review, we summarize the present knowledge on the oncogenic roles of EZH2 and its potential use as a therapeutic target, with special emphasis on BC pathogenesis and management. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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15 pages, 2008 KiB

Open AccessReview

PI3K and AKT: Unfaithful Partners in Cancer

by Seraina Faes and Olivier Dormond

Int. J. Mol. Sci. 2015, 16(9), 21138-21152; https://doi.org/10.3390/ijms160921138 - 3 Sep 2015

Cited by 227 | Viewed by 16428

Abstract

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway regulates multiple cellular processes. An overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression. Hence, its inhibition has become a promising approach in cancer therapy. However, the development [...] Read more.

The phosphatidylinositol 3-kinase (PI3K)/AKT signaling pathway regulates multiple cellular processes. An overactivation of the pathway is frequently present in human malignancies and plays a key role in cancer progression. Hence, its inhibition has become a promising approach in cancer therapy. However, the development of resistances, such as the abrogation of negative feedback mechanisms or the activation of other proliferative signaling pathways, has considerably limited the anticancer efficacy of PI3K/AKT inhibitors. In addition, emerging evidence points out that although AKT is acknowledged as the major downstream effector of PI3K, both PI3K and AKT can operate independently of each other in cancer, revealing another level of complexity in this pathway. Here, we highlight the complex relationship between PI3K and AKT in cancer and further discuss the consequences of this relationship for cancer therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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25 pages, 1213 KiB

Open AccessReview

Role of RUNX2 in Breast Carcinogenesis

by Daniel Wysokinski, Janusz Blasiak and Elzbieta Pawlowska

Int. J. Mol. Sci. 2015, 16(9), 20969-20993; https://doi.org/10.3390/ijms160920969 - 2 Sep 2015

Cited by 48 | Viewed by 9716

Abstract

RUNX2 is a transcription factor playing the major role in osteogenesis, but it can be involved in DNA damage response, which is crucial for cancer transformation. RUNX2 can interact with cell cycle regulators: cyclin-dependent kinases, pRB and p21Cip1 proteins, as well as the [...] Read more.

RUNX2 is a transcription factor playing the major role in osteogenesis, but it can be involved in DNA damage response, which is crucial for cancer transformation. RUNX2 can interact with cell cycle regulators: cyclin-dependent kinases, pRB and p21Cip1 proteins, as well as the master regulator of the cell cycle, the p53 tumor suppressor. RUNX2 is involved in many signaling pathways, including those important for estrogen signaling, which, in turn, are significant for breast carcinogenesis. RUNX2 can promote breast cancer development through Wnt and Tgfβ signaling pathways, especially in estrogen receptor (ER)-negative cases. ERα interacts directly with RUNX2 and regulates its activity. Moreover, the ERa gene has a RUNX2 binding site within its promoter. RUNX2 stimulates the expression of aromatase, an estrogen producing enzyme, increasing the level of estrogens, which in turn stimulate cell proliferation and replication errors, which can be turned into carcinogenic mutations. Exploring the role of RUNX2 in the pathogenesis of breast cancer can lead to revealing new therapeutic targets. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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32 pages, 996 KiB

Open AccessReview

Molecular Connections between Cancer Cell Metabolism and the Tumor Microenvironment

by Calvin R. Justus, Edward J. Sanderlin and Li V. Yang

Int. J. Mol. Sci. 2015, 16(5), 11055-11086; https://doi.org/10.3390/ijms160511055 - 15 May 2015

Cited by 114 | Viewed by 13940

Abstract

Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors [...] Read more.

Cancer cells preferentially utilize glycolysis, instead of oxidative phosphorylation, for metabolism even in the presence of oxygen. This phenomenon of aerobic glycolysis, referred to as the “Warburg effect”, commonly exists in a variety of tumors. Recent studies further demonstrate that both genetic factors such as oncogenes and tumor suppressors and microenvironmental factors such as spatial hypoxia and acidosis can regulate the glycolytic metabolism of cancer cells. Reciprocally, altered cancer cell metabolism can modulate the tumor microenvironment which plays important roles in cancer cell somatic evolution, metastasis, and therapeutic response. In this article, we review the progression of current understandings on the molecular interaction between cancer cell metabolism and the tumor microenvironment. In addition, we discuss the implications of these interactions in cancer therapy and chemoprevention. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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30 pages, 892 KiB

Open AccessReview

New Therapies for Dedifferentiated Papillary Thyroid Cancer

by Poupak Fallahi, Valeria Mazzi, Roberto Vita, Silvia Martina Ferrari, Gabriele Materazzi, David Galleri, Salvatore Benvenga, Paolo Miccoli and Alessandro Antonelli

Int. J. Mol. Sci. 2015, 16(3), 6153-6182; https://doi.org/10.3390/ijms16036153 - 17 Mar 2015

Cited by 49 | Viewed by 10097

Abstract

The number of thyroid cancers is increasing. Standard treatment usually includes primary surgery, thyroid-stimulating hormone suppressive therapy, and ablation of the thyroid remnant with radioactive iodine (RAI). Despite the generally good prognosis of thyroid carcinoma, about 5% of patients will develop metastatic disease, [...] Read more.

The number of thyroid cancers is increasing. Standard treatment usually includes primary surgery, thyroid-stimulating hormone suppressive therapy, and ablation of the thyroid remnant with radioactive iodine (RAI). Despite the generally good prognosis of thyroid carcinoma, about 5% of patients will develop metastatic disease, which fails to respond to RAI, exhibiting a more aggressive behavior. The lack of specific, effective and well-tolerated drugs, the scarcity of data about the association of multi-targeting drugs, and the limited role of radioiodine for dedifferentiated thyroid cancer, call for further efforts in the field of new drugs development. Rearranged during transfection (RET)/papillary thyroid carcinoma gene rearrangements, BRAF (B-RAF proto-oncogene, serine/threonine kinase) gene mutations, RAS (rat sarcoma) mutations, and vascular endothelial growth factor receptor 2 angiogenesis pathways are some of the known pathways playing a crucial role in the development of thyroid cancer. Targeted novel compounds have been demonstrated to induce clinical responses and stabilization of disease. Sorafenib has been approved for differentiated thyroid cancer refractory to RAI. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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16 pages, 1191 KiB

Open AccessReview

An Epigenetic Regulator: Methyl-CpG-Binding Domain Protein 1 (MBD1)

by Lu Li, Bi-Feng Chen and Wai-Yee Chan

Int. J. Mol. Sci. 2015, 16(3), 5125-5140; https://doi.org/10.3390/ijms16035125 - 5 Mar 2015

Cited by 39 | Viewed by 11552

Abstract

DNA methylation is an important form of epigenetic regulation in both normal development and cancer. Methyl-CpG-binding domain protein 1 (MBD1) is highly related to DNA methylation. Its MBD domain recognizes and binds to methylated CpGs. This binding allows it to trigger methylation of [...] Read more.

DNA methylation is an important form of epigenetic regulation in both normal development and cancer. Methyl-CpG-binding domain protein 1 (MBD1) is highly related to DNA methylation. Its MBD domain recognizes and binds to methylated CpGs. This binding allows it to trigger methylation of H3K9 and results in transcriptional repression. The CXXC3 domain of MBD1 makes it a unique member of the MBD family due to its affinity to unmethylated DNA. MBD1 acts as an epigenetic regulator via different mechanisms, such as the formation of the MCAF1/MBD1/SETDB1 complex or the MBD1-HDAC3 complex. As methylation status always changes along with carcinogenesis or neurogenesis, MBD1 with its interacting partners, including proteins and non-coding RNAs, participates in normal or pathological processes and functions in different regulatory systems. Because of the important role of MBD1 in epigenetic regulation, it is a good candidate as a therapeutic target for diseases. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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21 pages, 752 KiB

Open AccessReview

Roles of Ubiquitination and SUMOylation on Prostate Cancer: Mechanisms and Clinical Implications

by Zhenbang Chen and Wenfu Lu

Int. J. Mol. Sci. 2015, 16(3), 4560-4580; https://doi.org/10.3390/ijms16034560 - 27 Feb 2015

Cited by 46 | Viewed by 14492

Abstract

The initiation and progression of human prostate cancer are highly associated with aberrant dysregulations of tumor suppressors and proto-oncogenes. Despite that deletions and mutations of tumor suppressors and aberrant elevations of oncogenes at the genetic level are reported to cause cancers, emerging evidence [...] Read more.

The initiation and progression of human prostate cancer are highly associated with aberrant dysregulations of tumor suppressors and proto-oncogenes. Despite that deletions and mutations of tumor suppressors and aberrant elevations of oncogenes at the genetic level are reported to cause cancers, emerging evidence has revealed that cancer progression is largely regulated by posttranslational modifications (PTMs) and epigenetic alterations. PTMs play critical roles in gene regulation, cellular functions, tissue development, diseases, malignant progression and drug resistance. Recent discoveries demonstrate that ubiquitination and SUMOylation are complicated but highly-regulated PTMs, and make essential contributions to diseases and cancers by regulation of key factors and signaling pathways. Ubiquitination and SUMOylation pathways can be differentially modulated under various stimuli or stresses in order to produce the sustained oncogenic potentials. In this review, we discuss some new insights about molecular mechanisms on ubiquitination and SUMOylation, their associations with diseases, oncogenic impact on prostate cancer (PCa) and clinical implications for PCa treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology)

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21 pages, 1373 KiB

Open AccessReview

Tumor Progression Locus 2 (Tpl2) Kinase as a Novel Therapeutic Target for Cancer: Double-Sided Effects of Tpl2 on Cancer

by Hye Won Lee, Han Yong Choi, Kyeung Min Joo and Do-Hyun Nam

Int. J. Mol. Sci. 2015, 16(3), 4471-4491; https://doi.org/10.3390/ijms16034471 - 25 Feb 2015

Cited by 34 | Viewed by 9533

Abstract

Tumor progression locus 2 (Tpl2) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that conveys various intra- and extra-cellular stimuli to effector proteins of cells provoking adequate adoptive responses. Recent studies have elucidated that Tpl2 is an indispensable signal transducer as an [...] Read more.

Tumor progression locus 2 (Tpl2) is a mitogen-activated protein kinase (MAPK) kinase kinase (MAP3K) that conveys various intra- and extra-cellular stimuli to effector proteins of cells provoking adequate adoptive responses. Recent studies have elucidated that Tpl2 is an indispensable signal transducer as an MAP3K family member in diverse signaling pathways that regulate cell proliferation, survival, and death. Since tumorigenesis results from dysregulation of cellular proliferation, differentiation, and apoptosis, Tpl2 participates in many decisive molecular processes of tumor development and progression. Moreover, Tpl2 is closely associated with cytokine release of inflammatory cells, which has crucial effects on not only tumor cells but also tumor microenvironments. These critical roles of Tpl2 in human cancers make it an attractive anti-cancer therapeutic target. However, Tpl2 contradictorily works as a tumor suppressor in some cancers. The double-sided effects of Tpl2 originate from the specific upstream and downstream signaling environment of each tumor, since Tpl2 interacts with various signaling components. This review summarizes recent studies concerning the possible roles of Tpl2 in human cancers and considers its possibility as a therapeutic target, against which novel anti-cancer agents could be developed. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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16 pages, 717 KiB

Open AccessReview

Diverse Roles of SIRT1 in Cancer Biology and Lipid Metabolism

by Glenn E. Simmons, Jr., Wendy M. Pruitt and Kevin Pruitt

Int. J. Mol. Sci. 2015, 16(1), 950-965; https://doi.org/10.3390/ijms16010950 - 5 Jan 2015

Cited by 99 | Viewed by 15979

Abstract

SIRT1, an NAD⁺-dependent deacetylase, has been described in the literature as a major player in the regulation of cellular stress responses. Its expression has been shown to be altered in cancer cells, and it targets both histone and non-histone proteins for [...] Read more.

SIRT1, an NAD⁺-dependent deacetylase, has been described in the literature as a major player in the regulation of cellular stress responses. Its expression has been shown to be altered in cancer cells, and it targets both histone and non-histone proteins for deacetylation and thereby alters metabolic programs in response to diverse physiological stress. Interestingly, many of the metabolic pathways that are influenced by SIRT1 are also altered in tumor development. Not only does SIRT1 have the potential to regulate oncogenic factors, it also orchestrates many aspects of metabolism and lipid regulation and recent reports are beginning to connect these areas. SIRT1 influences pathways that provide an alternative means of deriving energy (such as fatty acid oxidation and gluconeogenesis) when a cell encounters nutritive stress, and can therefore lead to altered lipid metabolism in various pathophysiological contexts. This review helps to show the various connections between SIRT1 and major pathways in cellular metabolism and the consequence of SIRT1 deregulation on carcinogenesis and lipid metabolism. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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19 pages, 755 KiB

Open AccessReview

Battle Against Cancer: An Everlasting Saga of p53

by Qian Hao and William C. Cho

Int. J. Mol. Sci. 2014, 15(12), 22109-22127; https://doi.org/10.3390/ijms151222109 - 1 Dec 2014

Cited by 26 | Viewed by 12604

Abstract

Cancer is one of the most life-threatening diseases characterized by uncontrolled growth and spread of malignant cells. The tumor suppressor p53 is the master regulator of tumor cell growth and proliferation. In response to various stress signals, p53 can be activated and transcriptionally [...] Read more.

Cancer is one of the most life-threatening diseases characterized by uncontrolled growth and spread of malignant cells. The tumor suppressor p53 is the master regulator of tumor cell growth and proliferation. In response to various stress signals, p53 can be activated and transcriptionally induces a myriad of target genes, including both protein-encoding and non-coding genes, controlling cell cycle progression, DNA repair, senescence, apoptosis, autophagy and metabolism of tumor cells. However, around 50% of human cancers harbor mutant p53 and, in the majority of the remaining cancers, p53 is inactivated through multiple mechanisms. Herein, we review the recent progress in understanding the molecular basis of p53 signaling, particularly the newly identified ribosomal stress—p53 pathway, and the development of chemotherapeutics via activating wild-type p53 or restoring mutant p53 functions in cancer. A full understanding of p53 regulation will aid the development of effective cancer treatments. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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15 pages, 1018 KiB

Open AccessReview

Large Intervening Non-Coding RNA HOTAIR Is an Indicator of Poor Prognosis and a Therapeutic Target in Human Cancers

by Yanlan Yao, Jinming Li and Lunan Wang

Int. J. Mol. Sci. 2014, 15(10), 18985-18999; https://doi.org/10.3390/ijms151018985 - 20 Oct 2014

Cited by 74 | Viewed by 9364

Abstract

In the human genome, the fraction of protein-coding genes that are stably transcribed is only up to 2%, with the remaining numerous RNAs having no protein-coding function. These non-coding RNAs (ncRNAs) have received considerable attention in cancer research in recent years. Breakthroughs have [...] Read more.

In the human genome, the fraction of protein-coding genes that are stably transcribed is only up to 2%, with the remaining numerous RNAs having no protein-coding function. These non-coding RNAs (ncRNAs) have received considerable attention in cancer research in recent years. Breakthroughs have been made in understanding microRNAs and small interfering RNAs, but larger RNAs such as long ncRNAs (lncRNAs) remain an enigma. One lncRNA, HOX antisense intergenic RNA (HOTAIR), has been shown to be dysregulated in many types of cancer, including breast cancer, colorectal cancer, and hepatoma. HOTAIR functions as a regulatory molecule in a wide variety of biological processes. However, its mechanism of action has not been clearly elucidated. It is widely believed that HOTAIR mediates chromosomal remodeling and coordinates with polycomb repressive complex 2 (PRC2) to regulate gene expression. Further study of HOTAIR-related pathways and the role of HOTAIR in tumorigenesis and tumor progression may identify new treatment targets. In this review, we will focus on the characteristics of HOTAIR, as well as data pertaining to its mechanism and its association with cancers. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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18 pages, 1590 KiB

Open AccessReview

Pomegranate and Its Components as Alternative Treatment for Prostate Cancer

by Lei Wang and Manuela Martins-Green

Int. J. Mol. Sci. 2014, 15(9), 14949-14966; https://doi.org/10.3390/ijms150914949 - 25 Aug 2014

Cited by 66 | Viewed by 20657

Abstract

Prostate cancer is the second leading cause of cancer deaths in men in the United States. There is a major need for less toxic but yet effective therapies to treat prostate cancer. Pomegranate fruit from the tree Punica granatum has been used for [...] Read more.

Prostate cancer is the second leading cause of cancer deaths in men in the United States. There is a major need for less toxic but yet effective therapies to treat prostate cancer. Pomegranate fruit from the tree Punica granatum has been used for centuries for medicinal purposes and is described as “nature’s power fruit”. Recent research has shown that pomegranate juice (PJ) and/or pomegranate extracts (PE) significantly inhibit the growth of prostate cancer cells in culture. In preclinical murine models, PJ and/or PE inhibit growth and angiogenesis of prostate tumors. More recently, we have shown that three components of PJ, luteolin, ellagic acid and punicic acid together, have similar inhibitory effects on prostate cancer growth, angiogenesis and metastasis. Results from clinical trials are also promising. PJ and/or PE significantly prolonged the prostate specific antigen (PSA) doubling time in patients with prostate cancer. In this review we discuss data on the effects of PJ and PE on prostate cancer. We also discuss the effects of specific components of the pomegranate fruit and how they have been used to study the mechanisms involved in prostate cancer progression and their potential to be used in deterring prostate cancer metastasis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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9 pages, 943 KiB

Open AccessReview

Salmonella as an Innovative Therapeutic Antitumor Agent

by Wen-Wei Chang and Che-Hsin Lee

Int. J. Mol. Sci. 2014, 15(8), 14546-14554; https://doi.org/10.3390/ijms150814546 - 21 Aug 2014

Cited by 51 | Viewed by 8304

Abstract

Lack of specificity of the therapeutic agent is a primary limitation in the treatment of a tumor. The use of preferentially replicating bacteria as therapeutic agents is an innovative approach to tumor treatment. This is based on the observation that certain obligate or [...] Read more.

Lack of specificity of the therapeutic agent is a primary limitation in the treatment of a tumor. The use of preferentially replicating bacteria as therapeutic agents is an innovative approach to tumor treatment. This is based on the observation that certain obligate or facultative anaerobic bacteria are capable of multiplying selectively in tumors and inhibiting their growth. Bacteria have been employed as antitumor agents that are capable of preferentially amplifying within tumors and inhibiting their growth. Moreover, bacteria-derived factors have an immune-stimulation effect. Therefore, bacteria are able to transfer therapeutic genes into the tumor cells using their infective ability. Herein, we introduce the application of bacteria for tumor therapy and focus on Salmonella, which have been widely used for tumor therapy. Salmonella have mainly been applied as gene-delivery vectors, antitumor immune activators and tumor cell death inducers. This study will not only evaluate the therapeutic efficacy of Salmonella for the treatment of tumor but will also elucidate the mechanisms underlying the antitumor activities mediated by Salmonella, which involve host immune responses and cellular molecular responses. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology 2014)

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21 pages, 262 KiB

Open AccessReview

MicroRNAs Involved in Anti-Tumour Immunity

by Hong W. H. Yu, Daniel M. Y. Sze and William C. S. Cho

Int. J. Mol. Sci. 2013, 14(3), 5587-5607; https://doi.org/10.3390/ijms14035587 - 11 Mar 2013

Cited by 15 | Viewed by 7704

Abstract

MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a [...] Read more.

MicroRNAs (miRNAs) are a category of small RNAs that constitute a new layer of complexity to gene regulation within the cell, which has provided new perspectives in understanding cancer biology. The deregulation of miRNAs contributes critically to the development and pathophysiology of a number of cancers. miRNAs have been found to participate in cell transformation and multiplication by acting as tumour oncogenes or suppressors; therefore, harnessing miRNAs may provide promising cancer therapeutics. Another major function of miRNAs is their activity as critical regulatory vehicles eliciting important regulatory processes in anti-tumour immunity through their influence on the development, differentiation and activation of various immune cells of both innate and adaptive immunity. This review aims to summarise recent findings focusing on the regulatory mechanisms of the development, differentiation, and proliferative aspects of the major immune populations by a diverse profile of miRNAs and may enrich our current understanding of the involvement of miRNAs in anti-tumour immunity. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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27 pages, 856 KiB

Open AccessReview

Chemical Inhibitors and microRNAs (miRNA) Targeting the Mammalian Target of Rapamycin (mTOR) Pathway: Potential for Novel Anticancer Therapeutics

by Naif AlQurashi, Saeed M. Hashimi and Ming Q. Wei

Int. J. Mol. Sci. 2013, 14(2), 3874-3900; https://doi.org/10.3390/ijms14023874 - 13 Feb 2013

Cited by 37 | Viewed by 11875

Abstract

The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR [...] Read more.

The mammalian target of rapamycin (mTOR) is a critical regulator of many fundamental features in response to upstream cellular signals, such as growth factors, energy, stress and nutrients, controlling cell growth, proliferation and metabolism through two complexes, mTORC1 and mTORC2. Dysregulation of mTOR signalling often occurs in a variety of human malignant diseases making it a crucial and validated target in the treatment of cancer. Tumour cells have shown high susceptibility to mTOR inhibitors. Rapamycin and its derivatives (rapalogs) have been tested in clinical trials in several tumour types and found to be effective as anticancer agents in patients with advanced cancers. To block mTOR function, they form a complex with FKBP12 and then bind the FRB domain of mTOR. Furthermore, a new generation of mTOR inhibitors targeting ATP-binding in the catalytic site of mTOR showed potent and more selective inhibition. More recently, microRNAs (miRNA) have emerged as modulators of biological pathways that are essential in cancer initiation, development and progression. Evidence collected to date shows that miRNAs may function as tumour suppressors or oncogenes in several human neoplasms. The mTOR pathway is a promising target by miRNAs for anticancer therapy. Extensive studies have indicated that regulation of the mTOR pathway by miRNAs plays a major role in cancer progression, indicating a novel way to investigate the tumorigenesis and therapy of cancer. Here, we summarize current findings of the role of mTOR inhibitors and miRNAs in carcinogenesis through targeting mTOR signalling pathways and determine their potential as novel anti-cancer therapeutics. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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32 pages, 572 KiB

Open AccessReview

HGF–MET Cascade, a Key Target for Inhibiting Cancer Metastasis: The Impact of NK4 Discovery on Cancer Biology and Therapeutics

by Shinya Mizuno and Toshikazu Nakamura

Int. J. Mol. Sci. 2013, 14(1), 888-919; https://doi.org/10.3390/ijms14010888 - 7 Jan 2013

Cited by 45 | Viewed by 11378

Abstract

Hepatocyte growth factor (HGF) was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, [...] Read more.

Hepatocyte growth factor (HGF) was discovered in 1984 as a mitogen of rat hepatocytes in a primary culture system. In the mid-1980s, MET was identified as an oncogenic mutant protein that induces malignant phenotypes in a human cell line. In the early 1990s, wild-type MET was shown to be a functional receptor of HGF. Indeed, HGF exerts multiple functions, such as proliferation, morphogenesis and anti-apoptosis, in various cells via MET tyrosine kinase phosphorylation. During the past 20 years, we have accumulated evidence that HGF is an essential conductor for embryogenesis and tissue regeneration in various types of organs. Furthermore, we found in the mid-1990s that stroma-derived HGF is a major contributor to cancer invasion at least in vitro. Based on this background, we prepared NK4 as an antagonist of HGF: NK4 inhibits HGF-mediated MET tyrosine phosphorylation by competing with HGF for binding to MET. In vivo, NK4 treatments produced the anti-tumor outcomes in mice bearing distinct types of malignant cancers, associated with the loss in MET activation. There are now numerous reports showing that HGF-antagonists and MET-inhibitors are logical for inhibiting tumor growth and metastasis. Additionally, NK4 exerts anti-angiogenic effects, partly through perlecan-dependent cascades. This paper focuses on the chronology and significance of HGF-antagonisms in anti-tumor researches, with an interest in NK4 discovery. Tumor HGF–MET axis is now critical for drug resistance and cancer stem cell maintenance. Thus, oncologists cannot ignore this cascade for the future success of anti-metastatic therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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38 pages, 973 KiB

Open AccessReview

Mechanisms of Resistance to Endocrine Therapy in Breast Cancer: Focus on Signaling Pathways, miRNAs and Genetically Based Resistance

by Rocío García-Becerra, Nancy Santos, Lorenza Díaz and Javier Camacho

Int. J. Mol. Sci. 2013, 14(1), 108-145; https://doi.org/10.3390/ijms14010108 - 20 Dec 2012

Cited by 220 | Viewed by 18562

Abstract

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, [...] Read more.

Breast cancer is the most frequent malignancy diagnosed in women. Approximately 70% of breast tumors express the estrogen receptor (ER). Tamoxifen and aromatase inhibitors (AIs) are the most common and effective therapies for patients with ERα-positive breast cancer. Alone or combined with chemotherapy, tamoxifen significantly reduces disease progression and is associated with more favorable impact on survival in patients. Unfortunately, endocrine resistance occurs, either de novo or acquired during the course of the treatment. The mechanisms that contribute to hormonal resistance include loss or modification in the ERα expression, regulation of signal transduction pathways, altered expression of specific microRNAs, balance of co-regulatory proteins, and genetic polymorphisms involved in tamoxifen metabolic activity. Because of the clinical consequences of endocrine resistance, new treatment strategies are arising to make the cells sensitive to tamoxifen. Here, we will review the current knowledge on mechanisms of endocrine resistance in breast cancer cells. In addition, we will discuss novel therapeutic strategies to overcome such resistance. Undoubtedly, circumventing endocrine resistance should help to improve therapy for the benefit of breast cancer patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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16 pages, 257 KiB

Open AccessReview

Novel Molecular Targets for the Treatment of Gastroenteropancreatic Endocrine Tumors: Answers and Unsolved Problems

by Gabriele Capurso, Volker Fendrich, Maria Rinzivillo, Francesco Panzuto, Detlef K. Bartsch and Gianfranco Delle Fave

Int. J. Mol. Sci. 2013, 14(1), 30-45; https://doi.org/10.3390/ijms14010030 - 20 Dec 2012

Cited by 6 | Viewed by 6689

Abstract

As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the [...] Read more.

As more knowledge on molecular alterations favoring carcinogenesis and spreading of gastroenteropancreatic endocrine tumors has become available, a number of targeted agents interfering with key growth and angiogenic pathways have been explored in preclinical and clinical studies. The mTOR inhibitor Everolimus, and the multi-target antiangiogenetic agent Sunitinib, have been shown to be effective and thus have been approved by the FDA for treatment of pancreatic endocrine tumors. However, there is little data on the primary resistance to targeted agents on these tumors. The goals of the present review are to elucidate the possible advantage of combined treatments in overcoming induced resistances, and to identify biomarkers able to predict clinical efficacy. Moreover, the role of interesting targets for which a strong biological rationale exists, and specific inhibitors are available, such as the Src Family Kinases and the Hedgehog Pathway, are discussed. There is now need for more preclinical studies on cell lines and animal models to provide a stronger preclinical background in this field, as well as clinical trials specifically comparing one targeted therapy with another or combining different targeted agents. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

22 pages, 334 KiB

Open AccessReview

The Implications of Cancer Stem Cells for Cancer Therapy

by Wenjing Jiang, Jianhua Peng, Yue Zhang, William C. S. Cho and Kunlin Jin

Int. J. Mol. Sci. 2012, 13(12), 16636-16657; https://doi.org/10.3390/ijms131216636 - 5 Dec 2012

Cited by 50 | Viewed by 12440

Abstract

Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a [...] Read more.

Surgery, radiotherapy and chemotherapy are universally recognized as the most effective anti-cancer therapies. Despite significant advances directed towards elucidating molecular mechanisms and developing clinical trials, cancer still remains a major public health issue. Recent studies have showed that cancer stem cells (CSCs), a small subpopulation of tumor cells, can generate bulk populations of nontumorigenic cancer cell progeny through the self-renewal and differentiation processes. As CSCs are proposed to persist in tumors as a distinct population and cause relapse and metastasis by giving rise to new tumors, development of CSC-targeted therapeutic strategies holds new hope for improving survival and quality of life in patients with cancer. Therapeutic innovations will emerge from a better understanding of the biology and environment of CSCs, which, however, are largely unexplored. This review summarizes the characteristics, evidences and development of CSCs, as well as implications and challenges for cancer treatment. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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26 pages, 273 KiB

Open AccessReview

Drug Conjugates Such as Antibody Drug Conjugates (ADCs), Immunotoxins and Immunoliposomes Challenge Daily Clinical Practice

by Wolf-Dieter Janthur, Nathan Cantoni and Christoph Mamot

Int. J. Mol. Sci. 2012, 13(12), 16020-16045; https://doi.org/10.3390/ijms131216020 - 28 Nov 2012

Cited by 45 | Viewed by 9876

Abstract

Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical [...] Read more.

Drug conjugates have been studied extensively in preclinical in vitro and in vivo models but to date only a few compounds have progressed to the clinical setting. This situation is now changing with the publication of studies demonstrating a significant impact on clinical practice and highlighting the potential of this new class of targeted therapies. This review summarizes the pharmacological and molecular background of the main drug conjugation systems, namely antibody drug conjugates (ADCs), immunotoxins and immunoliposomes. All these compounds combine the specific targeting moiety of an antibody or similar construct with the efficacy of a toxic drug. The aim of this strategy is to target tumor cells specifically while sparing normal tissue, thus resulting in high efficacy and low toxicity. Recently, several strategies have been investigated in phase I clinical trials and some have entered phase III clinical development. This review provides a detailed overview of various strategies and critically discusses the most relevant achievements. Examples of the most advanced compounds include T-DM1 and brentuximab vedotin. However, additional promising strategies such as immunotoxins and immunoliposmes are already in clinical development. In summary, targeted drug delivery by drug conjugates is a new emerging class of anti-cancer therapy that may play a major role in the future. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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20 pages, 309 KiB

Open AccessReview

The Role of Vascular Endothelial Growth Factor A Polymorphisms in Breast Cancer

by Doonyapat Sa-nguanraksa and Pornchai O-charoenrat

Int. J. Mol. Sci. 2012, 13(11), 14845-14864; https://doi.org/10.3390/ijms131114845 - 13 Nov 2012

Cited by 43 | Viewed by 9992

Abstract

Breast cancer is the most common cancer in females and the leading cause of cancer death in women worldwide. Angiogenesis, the formation of new blood vessels, plays an important role in the development and progression of breast cancer. Vascular endothelial growth factor A [...] Read more.

Breast cancer is the most common cancer in females and the leading cause of cancer death in women worldwide. Angiogenesis, the formation of new blood vessels, plays an important role in the development and progression of breast cancer. Vascular endothelial growth factor A (VEGFA), the key modulator of angiogenesis, is highly expressed in cancer tissue and correlates with its more aggressive features. Polymorphisms of VEGFA alter the levels of expression and subsequently influence the susceptibility and aggressiveness of breast cancer. Assessment of VEGFA polymorphisms may be used for the identification of patients suitable for anti-VEGFA therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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17 pages, 769 KiB

Open AccessReview

Microenvironments and Cellular Characteristics in the Micro Tumor Cords of Malignant Solid Tumors

by Chan Joo Yeom, Yoko Goto, Yuxi Zhu, Masahiro Hiraoka and Hiroshi Harada

Int. J. Mol. Sci. 2012, 13(11), 13949-13965; https://doi.org/10.3390/ijms131113949 - 29 Oct 2012

Cited by 54 | Viewed by 9112

Abstract

Because of the accelerated proliferation of cancer cells and the limited distance that molecular oxygen can diffuse from functional tumor blood vessels, there appears to be a unique histology in malignant solid tumors, conglomerates of micro tumor cords. A functional blood vessel exists [...] Read more.

Because of the accelerated proliferation of cancer cells and the limited distance that molecular oxygen can diffuse from functional tumor blood vessels, there appears to be a unique histology in malignant solid tumors, conglomerates of micro tumor cords. A functional blood vessel exists at the center of each tumor cord and is sequentially surrounded by well-oxygenated, oxygen-insufficient, and oxygen-depleted cancer cells in the shape of baumkuchen (layered). Cancer cells, by inducing the expression of various genes, adapt to the highly heterogeneous microenvironments in each layer. Accumulated evidence has suggested that not only tumor microenvironments but also cellular adaptive responses to them, influence the radioresistance of cancer cells. However, precisely how these factors affect one another and eventually influence the therapeutic effect of radiation therapy remains to be elucidated. Here, based on recent basic and clinical cancer research, we deduced extrinsic (oxygen concentration, glucose concentration, pH etc.) and intrinsic (transcriptional activity of hypoxia-inducible factor 1, metabolic pathways, cell cycle status, proliferative activity etc.) parameters in each layer of a tumor cord. In addition, we reviewed the latest information about the molecular mechanism linking these factors with both tumor radioresistance and tumor recurrence after radiation therapy. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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11 pages, 165 KiB

Open AccessReview

The Criteria to Confirm the Role of Epstein-Barr Virus in Nasopharyngeal Carcinoma Initiation

by Ai-Di Gu, Mu-Sheng Zeng and Chao-Nan Qian

Int. J. Mol. Sci. 2012, 13(10), 13737-13747; https://doi.org/10.3390/ijms131013737 - 23 Oct 2012

Cited by 18 | Viewed by 7025

Abstract

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but it remains obscure whether EBV is a viral cause of, or only an accompaniment of, NPC. We will discuss the accumulated evidence pointing to the relationship between EBV infection and NPC initiation from [...] Read more.

Epstein-Barr virus (EBV) is associated with nasopharyngeal carcinoma (NPC), but it remains obscure whether EBV is a viral cause of, or only an accompaniment of, NPC. We will discuss the accumulated evidence pointing to the relationship between EBV infection and NPC initiation from epidemiologic, pathogenic, molecular oncogenic, and experimental animal studies. We believe that convincing evidence from these perspectives must be provided before we can ascertain the causal role of EBV infection in NPC. Specifically, (1) epidemiological studies should reveal EBV infection as a risk factor; (2) the introduction of EBV into an animal model should produce NPC; (3) in the animal model NPC, the main molecular event(s) or the involved signaling pathway(s) should be identical to that in human NPC; and (4) finally and most importantly, prevention of EBV infection or clearance of EBV from infected individuals must be able to reduce the incidence rate of NPC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

46 pages, 1085 KiB

Open AccessReview

Tanshinones: Sources, Pharmacokinetics and Anti-Cancer Activities

by Yong Zhang, Peixin Jiang, Min Ye, Sung-Hoon Kim, Cheng Jiang and Junxuan Lü

Int. J. Mol. Sci. 2012, 13(10), 13621-13666; https://doi.org/10.3390/ijms131013621 - 22 Oct 2012

Cited by 215 | Viewed by 15525

Abstract

Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have [...] Read more.

Tanshinones are a class of abietane diterpene compound isolated from Salvia miltiorrhiza (Danshen or Tanshen in Chinese), a well-known herb in Traditional Chinese Medicine (TCM). Since they were first identified in the 1930s, more than 40 lipophilic tanshinones and structurally related compounds have been isolated from Danshen. In recent decades, numerous studies have been conducted to investigate the isolation, identification, synthesis and pharmacology of tanshinones. In addition to the well-studied cardiovascular activities, tanshinones have been investigated more recently for their anti-cancer activities in vitro and in vivo. In this review, we update the herbal and alternative sources of tanshinones, and the pharmacokinetics of selected tanshinones. We discuss anti-cancer properties and identify critical issues for future research. Whereas previous studies have suggested anti-cancer potential of tanshinones affecting multiple cellular processes and molecular targets in cell culture models, data from in vivo potency assessment experiments in preclinical models vary greatly due to lack of uniformity of solvent vehicles and routes of administration. Chemical modifications and novel formulations had been made to address the poor oral bioavailability of tanshinones. So far, human clinical trials have been far from ideal in their design and execution for the purpose of supporting an anti-cancer indication of tanshinones. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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24 pages, 340 KiB

Open AccessReview

The Role of MicroRNAs in Breast Cancer Migration, Invasion and Metastasis

by Joy Tang, Aamir Ahmad and Fazlul H. Sarkar

Int. J. Mol. Sci. 2012, 13(10), 13414-13437; https://doi.org/10.3390/ijms131013414 - 18 Oct 2012

Cited by 167 | Viewed by 13668

Abstract

MicroRNAs (miRNAs) are a major class of small, noncoding RNA molecules that regulate gene expression by targeting mRNAs to trigger either translational repression or mRNA degradation. They have recently been more widely investigated due to their potential role as targets for cancer therapy. [...] Read more.

MicroRNAs (miRNAs) are a major class of small, noncoding RNA molecules that regulate gene expression by targeting mRNAs to trigger either translational repression or mRNA degradation. They have recently been more widely investigated due to their potential role as targets for cancer therapy. Many miRNAs have been implicated in several human cancers, including breast cancer. miRNAs are known to regulate cell cycle and development, and thus may serve as useful targets for exploration in anticancer therapeutics. The link between altered miRNA signatures and breast cancer development and metastasis can be observed either through the loss of tumor suppressor miRNAs, such as let-7s, miR-30a/31/34a/125s/200s/203/205/206/342 or the overexpression of oncogenic miRNAs, such as miR-10b/21/135a/155/221/222/224/373/520c in breast cancer cells. Some of these miRNAs have also been validated in tumor specimens of breast cancer patients, underscoring their potential roles in diagnostics, as well as targets for novel therapeutics for breast cancer. In this review article, we will provide an overview and update of our current understanding of the mode of action of several of these well characterized miRNAs in breast cancer models. Therefore, better understanding of the gene networks orchestrated by these miRNAs may help exploit the full potential of miRNAs in regards to cancer diagnosis, treatment, and therapeutics. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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24 pages, 233 KiB

Open AccessReview

The Behavior of Matrix Metalloproteinases and Their Inhibitors in Colorectal Cancer

by László Herszényi, István Hritz, Gábor Lakatos, Mária Zsófia Varga and Zsolt Tulassay

Int. J. Mol. Sci. 2012, 13(10), 13240-13263; https://doi.org/10.3390/ijms131013240 - 16 Oct 2012

Cited by 134 | Viewed by 10250

Abstract

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are [...] Read more.

Matrix metalloproteinases (MMPs) play an important role in the degradation of extracellular matrix components crucial for tumor growth, invasion and metastasis. MMPs are controlled by natural inhibitors called tissue inhibitors of metalloproteinases (TIMPs). We and others have demonstrated that MMPs and TIMPs are especially important in the process of tumor invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumor invasion and initiation of metastasis but also in carcinogenesis from colorectal adenomas. Several recent studies demonstrated that high preoperative serum or plasma MMP-2, MMP-9 and TIMP-1 antigen levels are strong predictive factors for poor prognosis in patients with CRC and their determination might be useful for identification of patients with higher risk for cancer recurrence. MMP-9 and TIMP-1 have significant potential tumor marker impact in CRC. Their diagnostic sensitivity is consistently higher than those of conventional biomarkers. The pharmacological targeting of CRC by the development of a new generation of selective inhibitors of MMPs, that is highly specific for certain MMPs, is a promising and challenging area for the future. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

17 pages, 204 KiB

Open AccessReview

The Complexities of Epidemiology and Prevention of Gastrointestinal Cancers

by Saba Haq, Shadan Ali, Ramzi Mohammad and Fazlul H. Sarkar

Int. J. Mol. Sci. 2012, 13(10), 12556-12572; https://doi.org/10.3390/ijms131012556 - 1 Oct 2012

Cited by 20 | Viewed by 7163

Abstract

Cancer epidemiology and prevention is one of the most well studied fields today. The more we can understand about the incidence and pathogenesis of this disease, the better we will be able to prevent it. Effective prevention strategies can decrease the mortality rate [...] Read more.

Cancer epidemiology and prevention is one of the most well studied fields today. The more we can understand about the incidence and pathogenesis of this disease, the better we will be able to prevent it. Effective prevention strategies can decrease the mortality rate of cancer significantly; this is why it is important to delineate the underlying causes. It has been well recognized that genetic mutations, sporadic or hereditary, may lead to increased chance of tumorigenesis. Detecting genetic mutations can lead to the identification of high-risk individuals with hereditary cancer syndromes, which may assist in devising prevention strategies. Further, environmental factors are known to play important roles in epidemiology and suggest prevention tools that could be implemented to reduce cancer incidence and subsequent cancer-associated morbidity and mortality. Chemoprevention has been tried in colon cancer and is finding new advancements in other carcinomas as well. Out of many environmental cancer preventive agents, the most notable developments are the identification of the role of vitamins E, vitamin D and folic acid. Increased consumption of these vitamins has shown to be inversely correlated with cancer risk. This review will highlight important aspects of cancer epidemiology in the most aggressive carcinomas of the gastrointestinal system focusing on colorectal adenocarcinoma and pancreatic adenocarcinoma. Additionally, some of the well-known and evolving aspects of epidemiology of colorectal and pancreatic cancer along with current and new prevention strategies will also be reviewed. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

12 pages, 183 KiB

Open AccessReview

MicroRNAs as Diagnostic Biomarkers in Gastric Cancer

by Ying Yin, Jun Li, Shujie Chen, Tianhua Zhou and Jianmin Si

Int. J. Mol. Sci. 2012, 13(10), 12544-12555; https://doi.org/10.3390/ijms131012544 - 1 Oct 2012

Cited by 41 | Viewed by 7129

Abstract

Considering the high mortality rates and the unfavorable prognosis of gastric cancer (GC) as well as the lack of a clinical predictive marker, which is sufficiently sensitive to GC, it is of great significance to investigate new sensitive and specific markers for GC [...] Read more.

Considering the high mortality rates and the unfavorable prognosis of gastric cancer (GC) as well as the lack of a clinical predictive marker, which is sufficiently sensitive to GC, it is of great significance to investigate new sensitive and specific markers for GC diagnosis. MicroRNAs (miRNAs) could be a practical form of potential biomarkers in the diagnosis of human disease, and they are confirmed to be closely associated with GC. In this review, we discuss the recent research results that indicate the feasibility and clinical applications of miRNAs in GC. Although several challenges remain to be addressed, miRNAs have the potential to be applied in the diagnosis of GC. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

28 pages, 314 KiB

Open AccessReview

Phosphoproteomics and Lung Cancer Research

by Elena López and William C. S. Cho

Int. J. Mol. Sci. 2012, 13(10), 12287-12314; https://doi.org/10.3390/ijms131012287 - 26 Sep 2012

Cited by 12 | Viewed by 8095

Abstract

Massive evidence suggests that genetic abnormalities contribute to the development of lung cancer. These molecular abnormalities may serve as diagnostic, prognostic and predictive biomarkers for this deadly disease. It is imperative to search these biomarkers in different tumorigenesis pathways so as to provide [...] Read more.

Massive evidence suggests that genetic abnormalities contribute to the development of lung cancer. These molecular abnormalities may serve as diagnostic, prognostic and predictive biomarkers for this deadly disease. It is imperative to search these biomarkers in different tumorigenesis pathways so as to provide the most appropriate therapy for each individual patient with lung malignancy. Phosphoproteomics is a promising technology for the identification of biomarkers and novel therapeutic targets for cancer. Thousands of proteins interact via physical and chemical association. Moreover, some proteins can covalently modify other proteins post-translationally. These post-translational modifications ultimately give rise to the emergent functions of cells in sequence, space and time. Phosphoproteomics clinical researches imply the comprehensive analysis of the proteins that are expressed in cells or tissues and can be employed at different stages. In addition, understanding the functions of phosphorylated proteins requires the study of proteomes as linked systems rather than collections of individual protein molecules. In fact, proteomics approaches coupled with affinity chromatography strategies followed by mass spectrometry have been used to elucidate relevant biological questions. This article will discuss the relevant clues of post-translational modifications, phosphorylated proteins, and useful proteomics approaches to identify molecular cancer signatures. The recent progress in phosphoproteomics research in lung cancer will be also discussed. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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16 pages, 1127 KiB

Open AccessReview

Prognostic and Predictive Roles of KRAS Mutation in Colorectal Cancer

by Amanda K. Arrington, Eileen L. Heinrich, Wendy Lee, Marjun Duldulao, Supriya Patel, Julian Sanchez, Julio Garcia-Aguilar and Joseph Kim

Int. J. Mol. Sci. 2012, 13(10), 12153-12168; https://doi.org/10.3390/ijms131012153 - 25 Sep 2012

Cited by 180 | Viewed by 21465

Abstract

The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of [...] Read more.

The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%–25% of all cancers. In particular, approximately 30%–40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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26 pages, 569 KiB

Open AccessReview

Personalized Targeted Therapy for Lung Cancer

by Kehua Wu, Larry House, Wanqing Liu and William C.S. Cho

Int. J. Mol. Sci. 2012, 13(9), 11471-11496; https://doi.org/10.3390/ijms130911471 - 13 Sep 2012

Cited by 61 | Viewed by 15451

Abstract

Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will [...] Read more.

Lung cancer has long been recognized as an extremely heterogeneous disease, since its development is unique in every patient in terms of clinical characterizations, prognosis, response and tolerance to treatment. Personalized medicine refers to the use of markers to predict which patient will most likely benefit from a treatment. In lung cancer, the well-developed epidermal growth factor receptor (EGFR) and the newly emerging EML4-anaplastic lymphoma kinase (ALK) are important therapeutic targets. This review covers the basic mechanism of EGFR and EML4-ALK activation, the predictive biomarkers, the mechanism of resistance, and the current targeted tyrosine kinase inhibitors. The efficacy of EGFR and ALK targeted therapies will be discussed in this review by summarizing the prospective clinical trials, which were performed in biomarker-based selected patients. In addition, the revolutionary sequencing and systems strategies will also be included in this review since these technologies will provide a comprehensive understanding in the molecular characterization of cancer, allow better stratification of patients for the most appropriate targeted therapies, eventually resulting in a more promising personalized treatment. The relatively low incidence of EGFR and ALK in non-Asian patients and the lack of response in mutant patients limit the application of the therapies targeting EGFR or ALK. Nevertheless, it is foreseeable that the sequencing and systems strategies may offer a solution for those patients. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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14 pages, 184 KiB

Open AccessReview

The Dual Role of Inflammation in Colon Carcinogenesis

by Giovanni Monteleone, Francesco Pallone and Carmine Stolfi

Int. J. Mol. Sci. 2012, 13(9), 11071-11084; https://doi.org/10.3390/ijms130911071 - 6 Sep 2012

Cited by 83 | Viewed by 8313

Abstract

Chronic inflammation characterizing patients with inflammatory bowel disease (IBD) represents a major risk factor for the development of colorectal cancer. Mechanisms underlying this neoplastic transformation are not fully understood though studies in experimental models of colon carcinogenesis suggest that inflammatory cell-derived cytokines either [...] Read more.

Chronic inflammation characterizing patients with inflammatory bowel disease (IBD) represents a major risk factor for the development of colorectal cancer. Mechanisms underlying this neoplastic transformation are not fully understood though studies in experimental models of colon carcinogenesis suggest that inflammatory cell-derived cytokines either directly or indirectly stimulate the uncontrolled growth of cancer cells. Nevertheless, under specific inflammatory conditions, immune cells can boost an anti-tumor immune response with the down-stream effect of eliminating dysplastic and cancerous cells. This review outlines the beneficial and detrimental role of inflammation in colon carcinogenesis. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

19 pages, 1754 KiB

Open AccessReview

Intravascular Targets for Molecular Contrast-Enhanced Ultrasound Imaging

by Siver A. Moestue, Ingrid S. Gribbestad and Rune Hansen

Int. J. Mol. Sci. 2012, 13(6), 6679-6697; https://doi.org/10.3390/ijms13066679 - 1 Jun 2012

Cited by 28 | Viewed by 9475

Abstract

Molecular targeting of contrast agents for ultrasound imaging is emerging as a new medical imaging modality. It combines advances in ultrasound technology with principles of molecular imaging, thereby allowing non-invasive assessment of biological processes in vivo. Preclinical studies have shown that microbubbles, [...] Read more.

Molecular targeting of contrast agents for ultrasound imaging is emerging as a new medical imaging modality. It combines advances in ultrasound technology with principles of molecular imaging, thereby allowing non-invasive assessment of biological processes in vivo. Preclinical studies have shown that microbubbles, which provide contrast during ultrasound imaging, can be targeted to specific molecular markers. These microbubbles accumulate in tissue with target (over) expression, thereby significantly increasing the ultrasound signal. This concept offers safe and low-cost imaging with high spatial resolution and sensitivity. It is therefore considered to have great potential in cancer imaging, and early-phase clinical trials are ongoing. In this review, we summarize the current literature on targets that have been successfully imaged in preclinical models using molecularly targeted ultrasound contrast agents. Based on preclinical experience, we discuss the potential clinical utility of targeted microbubbles. Full article

(This article belongs to the Special Issue Advances in Molecular Oncology (special issue))

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