International Journal of Molecular Sciences

Research

Jump to: Review

21 pages, 22219 KiB

Open AccessArticle

Scutellaria baicalensis Induces Cell Apoptosis and Elicits Mesenchymal–Epithelial Transition to Alleviate Metastatic Hepatocellular Carcinoma via Modulating HSP90β

by Tung-Ho Wu, Tung-Yi Lin, Pei-Ming Yang, Wen-Tai Li, Chau-Ting Yeh and Tai-Long Pan

Int. J. Mol. Sci. 2024, 25(5), 3073; https://doi.org/10.3390/ijms25053073 - 6 Mar 2024

Viewed by 875

Abstract

Hepatocellular carcinoma is one of the most common malignant tumors in the world and shows strong metastatic potential. Current medicine for hepatocellular carcinoma therapy is invalid, while Scutellaria baicalensis Georgi exhibits the pharmaceutical potential to treat liver diseases and liver cancer. Herein, we [...] Read more.

Hepatocellular carcinoma is one of the most common malignant tumors in the world and shows strong metastatic potential. Current medicine for hepatocellular carcinoma therapy is invalid, while Scutellaria baicalensis Georgi exhibits the pharmaceutical potential to treat liver diseases and liver cancer. Herein, we verified the inhibitory properties and the pivotal molecules regimented by Scutellaria baicalensis on advanced hepatocellular carcinoma. At first, the viability of SK-Hep-1 cells was significantly reduced under treatment of Scutellaria baicalensis extract in a dose-dependent manner without affecting the growth of normal hepatocyte. Scutellaria baicalensis extract application could remarkably cause apoptosis of SK-Hep-1 cells through p53/cytochrome C/poly-ADP ribose polymerase cascades and arrest the cell cycle at the G1/S phase by downregulating cyclin-dependent kinases. Meanwhile, administration of Scutellaria baicalensis extract remarkably attenuated the migration capability as well as suppressed matrix metalloproteinase activity of advanced hepatocellular carcinoma cells. The proteome profiles and network analysis particularly implied that exposure to Scutellaria baicalensis extract downregulated the expression of HSP90β, and the clinical stage of hepatocellular carcinoma is also positively correlated with the HSP90β level. Combined treatment of Scutellaria baicalensis extract and HSP90β siRNAs could markedly enhance the ubiquitination activity and the degradation of vimentin to subsequently inhibit the metastatic property of SK-Hep-1 cells. Moreover, application of Scutellaria baicalensis extract and HSP90β siRNAs depleted phosphorylation of AKT, which stimulated the expression of p53 and consecutively triggered cell apoptosis. These findings suggest that HSP90β may be a prospective target for the effective therapy of advanced hepatocellular carcinoma via accelerating apoptosis of hepatocellular carcinoma cells and eliciting mesenchymal–epithelial transition with the administration of Scutellaria baicalensis extract. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Figure 1

29 pages, 9978 KiB

Open AccessArticle

Dualistic Effects of PRKAR1A as a Potential Anticancer Target in Cancer Cells and Cancer-Derived Stem Cells

by Joong-Won Baek, A-Reum Nam, Kyunggon Kim and Pyung-Hwan Kim

Int. J. Mol. Sci. 2024, 25(5), 2876; https://doi.org/10.3390/ijms25052876 - 1 Mar 2024

Viewed by 592

Abstract

The integration of innovative medical technologies and interdisciplinary collaboration could improve the treatment of cancer, a globally prevalent and often deadly disease. Despite recent advancements, current cancer therapies fail to specifically address recurrence and target cancer stem cells (CSCs), which contribute to relapse. [...] Read more.

The integration of innovative medical technologies and interdisciplinary collaboration could improve the treatment of cancer, a globally prevalent and often deadly disease. Despite recent advancements, current cancer therapies fail to specifically address recurrence and target cancer stem cells (CSCs), which contribute to relapse. In this study, we utilized three types of cancer cells, from which three types of CSCs were further derived, to conduct a proteomic analysis. Additionally, shared cell surface biomarkers were identified as potential targets for a comprehensive treatment strategy. The selected biomarkers were evaluated through short hairpin RNA treatment, which revealed contrasting functions in cancer cells and CSCs. Knockdown of the identified proteins revealed that they regulate the epithelial–mesenchymal transition (EMT) and stemness via the ERK signaling pathway. Resistance to anticancer agents was consequently reduced, ultimately enhancing the overall anticancer effects of the treatment. Additionally, the significance of these biomarkers in clinical patient outcomes was confirmed using bioinformatics. Our study suggests a novel cancer treatment strategy that addresses the limitations of current anticancer therapies. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Figure 1

20 pages, 3939 KiB

Open AccessArticle

Transcriptome Profiling of Cardiac Glycoside Treatment Reveals EGR1 and Downstream Proteins of MAPK/ERK Signaling Pathway in Human Breast Cancer Cells

by Honey Pavithran, Ranjith Kumavath and Preetam Ghosh

Int. J. Mol. Sci. 2023, 24(21), 15922; https://doi.org/10.3390/ijms242115922 - 2 Nov 2023

Viewed by 1451

Abstract

Cardiac glycosides (CGs) constitute a group of steroid-like compounds renowned for their effectiveness in treating cardiovascular ailments. In recent times, there has been growing recognition of their potential use as drug leads in cancer treatment. In our prior research, we identified three highly [...] Read more.

Cardiac glycosides (CGs) constitute a group of steroid-like compounds renowned for their effectiveness in treating cardiovascular ailments. In recent times, there has been growing recognition of their potential use as drug leads in cancer treatment. In our prior research, we identified three highly promising CG compounds, namely lanatoside C (LC), peruvoside (PS), and strophanthidin (STR), which exhibited significant antitumor effects in lung, liver, and breast cancer cell lines. In this study, we investigated the therapeutic response of these CGs, with a particular focus on the MCF-7 breast cancer cell line. We conducted transcriptomic profiling and further validated the gene and protein expression changes induced by treatment through qRT-PCR, immunoblotting, and immunocytochemical analysis. Additionally, we demonstrated the interactions between the ligands and target proteins using the molecular docking approach. The transcriptome analysis revealed a cluster of genes with potential therapeutic targets involved in cytotoxicity, immunomodulation, and tumor-suppressor pathways. Subsequently, we focused on cross-validating the ten most significantly expressed genes, EGR1, MAPK1, p53, CCNK, CASP9, BCL2L1, CDK7, CDK2, CDK2AP1, and CDKN1A, through qRT-PCR, and their by confirming the consistent expression pattern with RNA-Seq data. Notably, among the most variable genes, we identified EGR1, the downstream effector of the MAPK signaling pathway, which performs the regulatory function in cell proliferation, tumor invasion, and immune regulation. Furthermore, we substantiated the influence of CG compounds on translational processes, resulting in an alteration in protein expression upon treatment. An additional analysis of ligand–protein interactions provided further evidence of the robust binding affinity between LC, PS, and STR and their respective protein targets. These findings underscore the intense anticancer activity of the investigated CGs, shedding light on potential target genes and elucidating the probable mechanism of action of CGs in breast cancer. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Graphical abstract

20 pages, 7522 KiB

Open AccessArticle

Identification of Molecular Subtypes and Prognostic Characteristics of Adrenocortical Carcinoma Based on Unsupervised Clustering

by Yuan Zhang, Cong Zhang, Kangjie Li, Jielian Deng, Hui Liu, Guichuan Lai, Biao Xie and Xiaoni Zhong

Int. J. Mol. Sci. 2023, 24(20), 15465; https://doi.org/10.3390/ijms242015465 - 23 Oct 2023

Viewed by 1208

Abstract

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Increasing evidence highlights the significant role of immune-related genes (IRGs) in ACC progression and immunotherapy, but the research is still limited. Based on the Cancer Genome Atlas (TCGA) database, immune-related molecular [...] Read more.

Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis. Increasing evidence highlights the significant role of immune-related genes (IRGs) in ACC progression and immunotherapy, but the research is still limited. Based on the Cancer Genome Atlas (TCGA) database, immune-related molecular subtypes were identified by unsupervised consensus clustering. Univariate Cox analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression were employed to further establish immune-related gene signatures (IRGS). An evaluation of immune cell infiltration, biological function, tumor mutation burden (TMB), predicted immunotherapy response, and drug sensitivity in ACC patients was conducted to elucidate the applicative efficacy of IRGS in precision therapy. ACC patients were divided into two molecular subtypes through consistent clustering. Furthermore, the 3-gene signature (including PRKCA, LTBP1, and BIRC5) based on two molecular subtypes demonstrated consistent prognostic efficacy across the TCGA and GEO datasets and emerged as an independent prognostic factor. The low-risk group exhibited heightened immune cell infiltration, TMB, and immune checkpoint inhibitors (ICIs), associated with a favorable prognosis. Pathways associated with drug metabolism, hormone regulation, and metabolism were activated in the low-risk group. In conclusion, our findings suggest IRGS can be used as an independent prognostic biomarker, providing a foundation for shaping future ACC immunotherapy strategies. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Figure 1

21 pages, 6200 KiB

Open AccessArticle

Development of a Macrophage-Related Risk Model for Metastatic Melanoma

by Zhaoxiang Li, Xinyuan Zhang, Quanxin Jin, Qi Zhang, Qi Yue, Manabu Fujimoto and Guihua Jin

Int. J. Mol. Sci. 2023, 24(18), 13752; https://doi.org/10.3390/ijms241813752 - 6 Sep 2023

Viewed by 1222

Abstract

As a metastasis-prone malignancy, the metastatic form and location of melanoma seriously affect its prognosis. Although effective surgical methods and targeted drugs are available to enable the treatment of carcinoma in situ, for metastatic tumors, the diagnosis, prognosis assessment and development of immunotherapy [...] Read more.

As a metastasis-prone malignancy, the metastatic form and location of melanoma seriously affect its prognosis. Although effective surgical methods and targeted drugs are available to enable the treatment of carcinoma in situ, for metastatic tumors, the diagnosis, prognosis assessment and development of immunotherapy are still pending. This study aims to integrate multiple bioinformatics approaches to identify immune-related molecular targets viable for the treatment and prognostic assessment of metastatic melanoma, thus providing new strategies for its use as an immunotherapy. Immunoinfiltration analysis revealed that M1-type macrophages have significant infiltration differences in melanoma development and metastasis. In total, 349 genes differentially expressed in M1-type macrophages and M2-type macrophages were extracted from the MSigDB database. Then we derived an intersection of these genes and 1111 melanoma metastasis-related genes from the GEO database, and 31 intersected genes identified as melanoma macrophage immunomarkers (MMIMs) were obtained. Based on MMIMs, a risk model was constructed using the Lasso algorithm and regression analysis, which contained 10 genes (NMI, SNTB2, SLC1A4, PDE4B, CLEC2B, IFI27, COL1A2, MAF, LAMP3 and CCDC69). Patients with high+ risk scores calculated via the model have low levels of infiltration by CD8⁺ T cells and macrophages, which implies a poor prognosis for patients with metastatic cancer. DCA decision and nomogram curves verify the high sensitivity and specificity of this model for metastatic cancer patients. In addition, 28 miRNAs, 90 transcription factors and 29 potential drugs were predicted by targeting the 10 MMIMs derived from this model. Overall, we developed and validated immune-related prognostic models, which accurately reflected the prognostic and immune infiltration characteristics of patients with melanoma metastasis. The 10 MMIMs may also be prospective targets for immunotherapy. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Figure 1

Review

Jump to: Research

28 pages, 3842 KiB

Open AccessReview

Squalene Epoxidase: Its Regulations and Links with Cancers

by Lin Zhang, Zheng Cao, Yuheng Hong, Haihua He, Leifeng Chen, Zhentao Yu and Yibo Gao

Int. J. Mol. Sci. 2024, 25(7), 3874; https://doi.org/10.3390/ijms25073874 - 30 Mar 2024

Viewed by 831

Abstract

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate–cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the [...] Read more.

Squalene epoxidase (SQLE) is a key enzyme in the mevalonate–cholesterol pathway that plays a critical role in cellular physiological processes. It converts squalene to 2,3-epoxysqualene and catalyzes the first oxygenation step in the pathway. Recently, intensive efforts have been made to extend the current knowledge of SQLE in cancers through functional and mechanistic studies. However, the underlying mechanisms and the role of SQLE in cancers have not been fully elucidated yet. In this review, we retrospected current knowledge of SQLE as a rate-limiting enzyme in the mevalonate–cholesterol pathway, while shedding light on its potential as a diagnostic and prognostic marker, and revealed its therapeutic values in cancers. We showed that SQLE is regulated at different levels and is involved in the crosstalk with iron-dependent cell death. Particularly, we systemically reviewed the research findings on the role of SQLE in different cancers. Finally, we discussed the therapeutic implications of SQLE inhibitors and summarized their potential clinical values. Overall, this review discussed the multifaceted mechanisms that involve SQLE to present a vivid panorama of SQLE in cancers. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Figure 1

19 pages, 5768 KiB

Open AccessReview

Qualitative and Quantitative Analytical Techniques of Nucleic Acid Modification Based on Mass Spectrometry for Biomarker Discovery

by Ying Liu, Jia-Hui Dong, Xu-Yang Shen, Yi-Xuan Gu, Run-Hong Zhang, Ruo-Yao Cui, Ya-Hong Liu, Jiang Zhou, Ying-Lin Zhou and Xin-Xiang Zhang

Int. J. Mol. Sci. 2024, 25(6), 3383; https://doi.org/10.3390/ijms25063383 - 16 Mar 2024

Viewed by 629

Abstract

Nucleic acid modifications play important roles in biological activities and disease occurrences, and have been considered as cancer biomarkers. Due to the relatively low amount of nucleic acid modifications in biological samples, it is necessary to develop sensitive and reliable qualitative and quantitative [...] Read more.

Nucleic acid modifications play important roles in biological activities and disease occurrences, and have been considered as cancer biomarkers. Due to the relatively low amount of nucleic acid modifications in biological samples, it is necessary to develop sensitive and reliable qualitative and quantitative methods to reveal the content of any modifications. In this review, the key processes affecting the qualitative and quantitative analyses are discussed, such as sample digestion, nucleoside extraction, chemical labeling, chromatographic separation, mass spectrometry detection, and data processing. The improvement of the detection sensitivity and specificity of analytical methods based on mass spectrometry makes it possible to study low-abundance modifications and their biological functions. Some typical nucleic acid modifications and their potential as biomarkers are displayed, and efforts to improve diagnostic accuracy are discussed. Future perspectives are raised for this research field. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Figure 1

20 pages, 3275 KiB

Open AccessReview

The Multifaceted Role of FUT8 in Tumorigenesis: From Pathways to Potential Clinical Applications

by Meng Shi, Xin-Rui Nan and Bao-Qin Liu

Int. J. Mol. Sci. 2024, 25(2), 1068; https://doi.org/10.3390/ijms25021068 - 15 Jan 2024

Viewed by 814

Abstract

FUT8, the sole glycosyltransferase responsible for N-glycan core fucosylation, plays a crucial role in tumorigenesis and development. Aberrant FUT8 expression disrupts the function of critical cellular components and triggers the abnormality of tumor signaling pathways, leading to malignant transformations such as proliferation, invasion, [...] Read more.

FUT8, the sole glycosyltransferase responsible for N-glycan core fucosylation, plays a crucial role in tumorigenesis and development. Aberrant FUT8 expression disrupts the function of critical cellular components and triggers the abnormality of tumor signaling pathways, leading to malignant transformations such as proliferation, invasion, metastasis, and immunosuppression. The association between FUT8 and unfavorable outcomes in various tumors underscores its potential as a valuable diagnostic marker. Given the remarkable variation in biological functions and regulatory mechanisms of FUT8 across different tumor types, gaining a comprehensive understanding of its complexity is imperative. Here, we review how FUT8 plays roles in tumorigenesis and development, and how this outcome could be utilized to develop potential clinical therapies for tumors. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures

Figure 1

19 pages, 5906 KiB

Open AccessReview

Heat Shock Proteins and Breast Cancer

by Miao Zhang and Xiaowen Bi

Int. J. Mol. Sci. 2024, 25(2), 876; https://doi.org/10.3390/ijms25020876 - 10 Jan 2024

Cited by 1 | Viewed by 1347

Abstract

Heat shock proteins (Hsps) are a group of stress-induced proteins involved in protein folding and maturation. Based on their molecular weight, Hsps can be divided into six families: small Hsps, Hsp40, Hsp60, Hsp70, Hsp90, and large Hsps. In the process of breast cancer [...] Read more.

Heat shock proteins (Hsps) are a group of stress-induced proteins involved in protein folding and maturation. Based on their molecular weight, Hsps can be divided into six families: small Hsps, Hsp40, Hsp60, Hsp70, Hsp90, and large Hsps. In the process of breast cancer tumorigenesis, Hsps play a central role in regulating cell reactions and functions including proliferation, metastasis, and apoptosis. Moreover, some of the critical Hsps also regulate the fine balance between the protective and destructive immunological responses within the tumor microenvironment. In this review, we systematically summarize the roles of major Hsps in breast cancer biology and point out the potential uses of these proteins in breast cancer diagnosis and therapy. Understanding the roles of different families of Hsps in breast cancer pathogenesis will help in the development of more effective prevention and treatment measures for breast cancer. Full article

(This article belongs to the Special Issue Advance in Cancer Biomarker: From Molecular Mechanisms to Potential Therapy)

► Show Figures