Special Issue "Genes and Pathways in the Pathogenesis of Ovarian Cancer"
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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology".
Deadline for manuscript submissions: 30 July 2013
Special Issue Editor
Guest Editor
Prof. Dr. Ie-Ming Shih
Department of Pathology, Faculty in Pathobiology PhD Graduate Program, Johns Hopkins University, School of Medicine, CRB-II, Rm 305, 1550 Orleans Street, Baltimore, Maryland 21231, USA
Website: http://pathology2.jhu.edu/shihlab/index.cfm
E-Mail: ishih@jhmi.edu
Phone: +1 410 502 7774
Fax: +1 410 502 7943
Interests: cancer pathogenesis; gene amplification; gene mutation; differential diagnosis; genome-wide analysis of human cancer
Special Issue Information
Dear Colleagues,
Ovarian cancer is one of the most aggressive neoplastic diseases in women. It is composed of distinct types of carcinoma with unique clinicopathological and molecular features. The genome-wide molecular genetic landscape in various histological subtypes of ovarian cancer has been recently revealed through the effort of The Cancer Genome Atlas and other investigator-initiated genomic analyses. Those database resources provide an unprecedented opportunity for basic research to understand pathogenesis of ovarian cancer and for translational research that may lead to new diagnosis and treatment. There are several prioritized research areas that need to be addressed in this devastating disease. Thus, this special issue offers a timely opportunity to publish those studies that aim at exploring the molecular and translational aspects of ovarian cancer. Both original research and review articles are all welcome, especially for those articles describing genes and pathways that may serve as new targets for experimental therapeutics and future clinical trials. It is expected that this new special issue will become a useful resource for all investigators and clinicians who are interested in ovarian cancer research and will inspire new research directions in the years to come.
Prof. Dr. Ie-Ming Shih
Guest Editor
Submission
Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. Papers will be published continuously (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.
Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are refereed through a peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed Open Access monthly journal published by MDPI.
Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1600 CHF.
Keywords
- ovarian cancer
- pathogenesis
- TCGA
- cancer genomics
- personalized medicine
- signaling pathways
Published Papers (22 papers)
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Received: 27 September 2012 / Accepted: 18 October 2012 / Published: 26 October 2012
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Abstract: The role of the forkhead box Q1 (FOXQ1) transcription factor in cancer pathogenesis has recently emerged. Overexpression of FOXQ1 has been found in a variety of human cancers, and its upregulation has been associated with poor prognosis in colorectal, breast, and non-small cell lung carcinomas. However, the molecular mechanism underlying how FOXQ1 contributes to ovarian epithelial carcinomas remains unclear. To this end, we analyzed gene expression levels in ovarian cancer tissues and cell lines and demonstrated a higher expression level of FOXQ1 in epithelial ovarian cancer cells than that in normal epithelial cells. We then used a human ovarian cancer cell line, SKOV3, which expressed a higher level of FOXQ1, as a cell model to investigate the biological effects of FOXQ1 by using RNA interference. Silencing of FOXQ1 expression using a shRNA knockdown approach affected the expression of several cell cycle regulators, leading to suppressed cell proliferation, reduced cell motility/invasion, and upregulation of epithelial cell markers and the downregulation of mesenchymal cell markers. Taken together, these results suggest that FOXQ1 expression is essential to maintain cell proliferation, motility/invasion, and epithelial-mesenchymal transition phenotypes in ovarian cancer cells.
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Received: 17 December 2012; in revised form: 30 December 2012 / Accepted: 5 January 2013 / Published: 9 January 2013
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Abstract: Despite advances in surgical and chemotherapeutic treatment options, less than 50% of patients with advanced-stage ovarian cancer survive five years after initial diagnosis. In this regard, novel treatment approaches are warranted utilizing molecularly targeted therapies directed against particular components of specific signaling pathways which are required for tumor development and progression. One molecular pathway of interest is the hedgehog (Hh) signaling pathway. Activation of the Hh pathway has been observed in several cancer types, including ovarian cancer. This review highlights the crucial role of Hh signaling in the development and progression of ovarian cancer and might lead to a better understanding of the Hh signaling in ovarian tumorigenesis, thus encouraging the investigation of novel targeted therapies.
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Alexandros Laios, Bashir M. Mohamed, Lynne Kelly, Richard Flavin, Stephen Finn, Lynda McEvoy, Michael Gallagher, Cara Martin, Orla Sheils, Martina Ring, Anthony Davies, Margaret Lawson, Noreen Gleeson, Tom D'Arcy, Charles d'Adhemar, Lucy Norris, Ream Langhe, Feras Abu Saadeh, John J. O'Leary and Sharon A. O'Toole
Received: 7 November 2012; in revised form: 5 January 2013 / Accepted: 6 January 2013 / Published: 22 January 2013
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Abstract: Platinum resistance is a major cause of treatment failure in ovarian cancer. We previously identified matrix metalloproteinase 9 (MMP-9) as a potential therapeutic target of chemoresistant disease. A2780cis (cisplatin-resistant) and A2780 (cisplatin-sensitive) ovarian carcinoma cell lines were used. The cytotoxic effect of MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) alone or in combination with cisplatin was determined using high content screening. Protein expression was examined using immunohistochemistry and ELISA. Co-incubation of cisplatin and an MMP-9/MMP-2 inhibitor, (2R)-2-[(4-Biphenylsulfonyl) amino]-3 phenylpropionic acid (C21H19NO4S) resulted in significantly greater cytotoxicity as compared to either treatment alone in a cisplatin resistant MMP-9 overexpressing cell line; A2780cis. In addition, pre-incubating with MMP-9i prior to cisplatin further enhances the cytotoxic effect. No significant difference was observed in MMP-9 protein in tissue but a trend towards increased MMP-9 was observed in recurrent serum. We propose that MMP-9/MMP-2i may be utilized in the treatment of recurrent/chemoresistant ovarian cancers that overexpress MMP-9 mRNA but its role in vivo remains to be evaluated.
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Received: 16 January 2013; in revised form: 25 January 2013 / Accepted: 28 January 2013 / Published: 1 February 2013
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Abstract: Approximately 25,000 ovarian cancers are diagnosed in the U.S. annually, and 75% are in the advanced stage and largely incurable. There is critical need for early detection tools and novel treatments. Proteasomal ubiquitin receptor ADRM1 is a protein that is encoded by the ADRM1 gene. Recently, we showed that among 20q13-amplified genes in ovarian cancer, ADRM1 overexpression was the most highly correlated with amplification and was significantly upregulated with respect to stage, recurrence, and metastasis. Its overexpression correlated significantly with shorter time to recurrence and overall survival. Array-CGH and microarray expression of ovarian cancer cell lines provided evidence consistent with primary tumor data that ADRM1 is a 20q13 amplification target. Herein, we confirm the ADRM1 amplicon in a second ovarian cancer cohort and define a minimally amplified region of 262 KB encompassing seven genes. Additionally, using RNAi knock-down of ADRM1 in naturally amplified cell line OAW42 and overexpression of ADRM1 via transfection in ES2, we show that (1) ADRM1 overexpression increases proliferation, migration, and growth in soft agar, and (2) knock-down of ADRM1 results in apoptosis. Proteomic analysis of cells with ADRM1 knock-down reveals dysregulation of proteins including CDK-activating kinase assembly factor MAT1. Taken together, the results indicate that amplified ADRM1 is involved in cell proliferation, migration and survival in ovarian cancer cells, supporting a role as an oncogene and novel therapeutic target for ovarian cancer.
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Received: 31 January 2013; in revised form: 21 February 2013 / Accepted: 25 February 2013 / Published: 28 February 2013
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Abstract: Ovarian cancer is the most lethal gynecological malignancy affecting American women. The gonadotropins, follicle stimulating hormone (FSH) and luteinizing hormone (LH), have been implicated as growth factors in ovarian cancer. In the present study, pathways activated by FSH and LH in normal ovarian surface epithelium (OSE) grown in their microenvironment were investigated. Gonadotropins increased proliferation in both three-dimensional (3D) ovarian organ culture and in a two-dimensional (2D) normal mouse cell line. A mouse cancer pathway qPCR array using mRNA collected from 3D organ cultures identified Akt as a transcriptionally upregulated target following stimulation with FSH, LH and the combination of FSH and LH. Activation of additional pathways, such as Birc5, Cdk2, Cdk4, and Cdkn2a identified in the 3D organ cultures, were validated by western blot using the 2D cell line. Akt and epidermal growth factor receptor (EGFR) inhibitors blocked gonadotropin-induced cell proliferation in 3D organ and 2D cell culture. OSE isolated from 3D organ cultures stimulated with LH or hydrogen peroxide initiated growth in soft agar. Hydrogen peroxide stimulated colonies were further enhanced when supplemented with FSH. LH colony formation and FSH promotion were blocked by Akt and EGFR inhibitors. These data suggest that the gonadotropins stimulate some of the same proliferative pathways in normal OSE that are activated in ovarian cancers.
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Received: 30 January 2013; in revised form: 21 February 2013 / Accepted: 26 February 2013 / Published: 6 March 2013
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Abstract: Endometriosis is classically defined as the presence of endometrial glands and stroma outside of the endometrial lining and uterine musculature. With an estimated frequency of 5%–10% among women of reproductive age, endometriosis is a common gynecologic disorder. While in itself a benign lesion, endometriosis shares several characteristics with invasive cancer, has been shown to undergo malignant transformation, and has been associated with an increased risk of epithelial ovarian carcinoma (EOC). Numerous epidemiologic studies have shown an increased risk of EOC among women with endometriosis. This is particularly true for women with endometrioid and clear cell ovarian carcinoma. However, the carcinogenic pathways by which endometriosis associated ovarian carcinoma (EAOC) develops remain poorly understood. Current molecular studies have sought to link endometriosis with EAOC through pathways related to oxidative stress, inflammation and hyperestrogenism. In addition, numerous studies have sought to identify an intermediary lesion between endometriosis and EAOC that may allow for the identification of endometriosis at greatest risk for malignant transformation or for the prevention of malignant transformation of this common gynecologic disorder. The objective of the current article is to review the current data regarding the molecular events associated with EAOC development from endometriosis, with a primary focus on malignancies of the endometrioid and clear cell histologic sub-types.
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Received: 29 January 2013; in revised form: 28 February 2013 / Accepted: 1 March 2013 / Published: 8 March 2013
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Abstract: Mirk/dyrk1B kinase is expressed in about 75% of resected human ovarian cancers and in most ovarian cancer cell lines with amplification in the OVCAR3 line. Mirk (minibrain-related kinase) is a member of the Minibrain/dyrk family of related serine/threonine kinases. Mirk maintains cells in a quiescent state by stabilizing the CDK inhibitor p27 and by inducing the breakdown of cyclin D isoforms. Mirk also stabilizes the DREAM complex, which maintains G0 quiescence by sequestering transcription factors needed to enter cycle. By entering a quiescent state, tumor cells can resist the nutrient deficiencies, hypoxic and acidic conditions within the tumor mass. Mirk maintains the viability of quiescent ovarian cancer cells by reducing intracellular levels of reactive oxygen species. CDKN2A-negative ovarian cancer cells treated with a Mirk kinase inhibitor escaped G0/G1 quiescence, entered cycle with high ROS levels and underwent apoptosis. The ROS scavenger N-acetyl cysteine reduced the extent of cancer cell loss. In contrast, the Mirk kinase inhibitor slightly reduced the fraction of G0 quiescent diploid epithelial cells and fibroblasts, and the majority of the cells pushed into cycle accumulated in G2 + M. Apoptotic sub-G0/G1 cells were not detected. Thus, normal cells were spared because of their expression of CDK inhibitors that blocked unregulated cycling and Mirk kinase inhibitor-treated normal diploid cells were about as viable as untreated controls.
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Received: 16 January 2013; in revised form: 25 February 2013 / Accepted: 26 February 2013 / Published: 15 March 2013
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Abstract: Ovarian cancer is one of the primary causes of death for women all through the Western world. Baicalin and baicalein are naturally occurring flavonoids that are found in the roots and leaves of some Chinese medicinal plants and are thought to have antioxidant activity and possible anti-angiogenic, anti-cancer, anxiolytic, anti-inflammatory and neuroprotective activities. Two kinds of ovarian cancer (OVCAR-3 and CP-70) cell lines and a normal ovarian cell line (IOSE-364) were selected to be investigated in the inhibitory effect of baicalin and baicalein on cancer cells. Largely, baicalin and baicalein inhibited ovarian cancer cell viability in both ovarian cancer cell lines with LD50 values in the range of 45–55 µM for baicalin and 25–40 µM for baicalein. On the other hand, both compounds had fewer inhibitory effects on normal ovarian cells viability with LD50 values of 177 µM for baicalin and 68 µM for baicalein. Baicalin decreased expression of VEGF (20 µM), cMyc (80 µM), and NFkB (20 µM); baicalein decreased expression of VEGF (10 µM), HIF-1α (20 µM), cMyc (20 µM), and NFkB (40 µM). Therefore baicalein is more effective in inhibiting cancer cell viability and expression of VEGF, HIF-1α, cMyc, and NFκB in both ovarian cancer cell lines. It seems that baicalein inhibited cancer cell viability through the inhibition of cancer promoting genes expression including VEGF, HIF-1α, cMyc, and NFκB. Overall, this study showed that baicalein and baicalin significantly inhibited the viability of ovarian cancer cells, while generally exerting less of an effect on normal cells. They have potential for chemoprevention and treatment of ovarian cancers.
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Received: 22 January 2013; in revised form: 7 February 2013 / Accepted: 25 February 2013 / Published: 15 March 2013
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Abstract: HE4, also known as WFDC2, is a useful biomarker for ovarian cancer when either used alone or in combination with CA125. HE4 is also overexpressed in endometrial cancer (EC), but its function in cancer cells is not clear. In this study, we investigate the role of HE4 in EC progression. An HE4-overexpression system was established by cloning the HE4 prototypic mRNA variant (HE4-V0) into a eukaryotic expression vector. Following transfection, stable clones in two EC cell lines were selected. The effects of HE4 overexpression on cell growth and function were measured with the use of cell proliferation assay, matrigel invasion, and soft agar gel colony formation assays. HE4-induced cancer cell proliferation in vivo was examined in a mouse xenograft model. HE4 overexpression significantly enhanced EC cell proliferation, matrigel invasion, and colony formation in soft agar. Moreover, HE4 overexpression promoted tumor growth in the mouse xenograft model. HE4 overexpression enhanced several malignant phenotypes in cell culture and in a mouse model. These results are consistent with our previous observation that high levels of serum HE4 closely correlate with the stage, myometrial invasion and tumor size in patients with EC. This study provides evidence that HE4 overexpression directly impacts tumor progression in endometrial cancer.
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Received: 17 February 2013; in revised form: 11 March 2013 / Accepted: 12 March 2013 / Published: 15 March 2013
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Abstract: Ovarian cancer treatment presently does not reflect molecular differences in histologic subtype. Ovarian clear cell carcinoma (OCCC) exhibits several differences in terms of molecular pathogenesis and tumor behavior from the more common, chemosensitive, serous carcinomas, which makes OCCC a candidate for targeted therapies. A 53-year-old Japanese woman was diagnosed with stage IIIc ovarian clear cell adenocarcinoma with marked chemoresistance to conventional regimens. She demonstrated a partial response to a multikinase inhibitor. The tumor was resistant to PI3K/mTOR pathway inhibitors despite harboring a PIK3CA mutation. The present case suggests a role for targeted therapies in the treatment of OCCC and a need for the identification of biomarkers that will predict response to targeted therapies.
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Received: 25 January 2013; in revised form: 5 March 2013 / Accepted: 13 March 2013 / Published: 15 March 2013
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Abstract: PAX2 is one of nine PAX genes that regulate tissue development and cellular differentiation in embryos. However, the functional role of PAX2 in ovarian cancer is not known. Twenty-six ovarian cancer cell lines with different histology origins were screened for PAX2 expression. Two ovarian cancer cell lines: RMUGL (mucinous) and TOV21G (clear cell), with high PAX2 expression were chosen for further study. Knockdown PAX2 expression in these cell lines was achieved by lentiviral shRNAs targeting the PAX2 gene. PAX2 stable knockdown cells were characterized for cell proliferation, migration, apoptosis, protein profiles, and gene expression profiles. The result indicated that these stable PAX2 knockdown cells had reduced cell proliferation and migration. Microarray analysis indicated that several genes involved in growth inhibition and motility, such as G0S2, GREM1, and WFDC1, were up-regulated in PAX2 knockdown cells. On the other hand, over-expressing PAX2 in PAX2-negative ovarian cell lines suppressed their cell proliferation. In summary, PAX2 could have both oncogenic and tumor suppression functions, which might depend on the genetic content of the ovarian cancer cells. Further investigation of PAX2 in tumor suppression and mortality is warranty.
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Received: 1 February 2013; in revised form: 11 March 2013 / Accepted: 19 March 2013 / Published: 25 March 2013
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Abstract: High grade serous ovarian cancer (HGSC), the most lethal and frequent type of epithelial ovarian cancer (EOC), has poor long term prognosis due to a combination of factors: late detection, great metastatic potential and the capacity to develop resistance to available therapeutic drugs. Furthermore, there has been considerable controversy concerning the etiology of this malignancy. New studies, both clinical and molecular, strongly suggest that HGSC originates not from the surface of the ovary, but from the epithelial layer of the neighboring fallopian tube fimbriae. In this paper we summarize data supporting the central role of fallopian tube epithelium in the development of HGSC. Specifically, we address cellular pathways and regulatory mechanisms which are modulated in the process of transformation, but also genetic changes which accumulate during disease progression. Similarities between fallopian tube mucosa and the malignant tissue of HGSC warrant a closer analysis of homeostatic mechanisms in healthy epithelium in order to elucidate key steps in disease development. Finally, we highlight the importance of the cancer stem cell (CSC) identification and understanding of its niche regulation for improvement of therapeutic strategies.
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Received: 16 February 2013; in revised form: 8 March 2013 / Accepted: 12 March 2013 / Published: 25 March 2013
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Abstract: Cancer stem cells or tumor-initiating cells (CSC/TICs), which can undergo self-renewal and differentiation, are thought to play critical roles in tumorigenesis, therapy resistance, tumor recurrence and metastasis. Tumor recurrence and chemoresistance are major causes of poor survival rates of ovarian cancer patients, which may be due in part to the existence of CSC/TICs. Therefore, elucidating the molecular mechanisms responsible for the ovarian CSC/TICs is required to develop a cure for this malignancy. Recent studies have indicated that the properties of CSC/TICs can be regulated by microRNAs, genes and signaling pathways which also function in normal stem cells. Moreover, emerging evidence suggests that the tumor microenvironments surrounding CSC/TICs are crucial for the maintenance of these cells. Similarly, efforts are now being made to unravel the mechanism involved in the regulation of ovarian CSC/TICs, although much work is still needed. This review considers recent advances in identifying the genes and pathways involved in the regulation of ovarian CSC/TICs. Furthermore, current approaches targeting ovarian CSC/TICs are described. Targeting both CSC/TICs and bulk tumor cells is suggested as a more effective approach to eliminating ovarian tumors. Better understanding of the regulation of ovarian CSC/TICs might facilitate the development of improved therapeutic strategies for recurrent ovarian cancer.
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Received: 1 February 2013; in revised form: 6 March 2013 / Accepted: 7 March 2013 / Published: 10 April 2013
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Abstract: Ovarian cancer remains the most lethal gynaecological cancer. A better understanding of the molecular pathogenesis of ovarian cancer is of critical importance to develop early detection tests and identify new therapeutic targets that would increase survival. Cancer cells depend on de novo lipid synthesis for the generation of fatty acids to meet the energy requirements for increased tumour growth. There is increasing evidence that lipid metabolism is deregulated in cancers, including ovarian cancer. The increased expression and activity of lipogenic enzymes is largely responsible for increased lipid synthesis, which is regulated by metabolic and oncogenic signalling pathways. This article reviews the latest knowledge on lipid metabolism and the alterations in the expression of lipogenic enzymes and downstream signalling pathways in ovarian cancer. Current developments for exploiting lipids as biomarkers for the detection of early stage ovarian cancer and therapeutic targets are discussed. Current research targeting lipogenic enzymes and lipids to increase the cytotoxicity of chemotherapy drugs is also highlighted.
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Received: 27 February 2013; in revised form: 28 March 2013 / Accepted: 1 April 2013 / Published: 15 April 2013
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Abstract: Ovarian cancer is the fifth most common cause of death due to cancer in women despite being the tenth in incidence. Unfortunately, the five-year survival rate is only 45%, which has not improved much in the past 30 years. Even though the majority of women have successful initial therapy, the low rate of survival is due to the eventual recurrence and succumbing to their disease. With the recent release of the Cancer Genome Atlas for ovarian cancer, it was shown that the PI3K/AKT/mTOR pathway was one of the most frequently mutated or altered pathways in patients’ tumors. Researching how the PI3K/AKT/mTOR pathway affects the progression and tumorigensis of ovarian cancer will hopefully lead to new therapies that will increase survival for women. This review focuses on recent research on the PI3K/AKT/mTOR pathway and its role in the progression and tumorigensis of ovarian cancer.
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Received: 1 February 2013; in revised form: 11 March 2013 / Accepted: 2 April 2013 / Published: 15 April 2013
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Abstract: The study of the ovarian proteomic profile represents a new frontier in ovarian cancer research, since this approach is able to enlighten the wide variety of post-translational events (such as glycosylation and phosphorylation). Due to the possibility of analyzing thousands of proteins, which could be simultaneously altered, comparative proteomics represent a promising model of possible biomarker discovery for ovarian cancer detection and monitoring. Moreover, defining signaling pathways in ovarian cancer cells through proteomic analysis offers the opportunity to design novel drugs and to optimize the use of molecularly targeted agents against crucial and biologically active pathways. Proteomic techniques provide more information about different histological types of ovarian cancer, cell growth and progression, genes related to tumor microenvironment and specific molecular targets predictive of response to chemotherapy than sequencing or microarrays. Estimates of specificity with proteomics are less consistent, but suggest a new role for combinations of biomarkers in early ovarian cancer diagnosis, such as the OVA1 test. Finally, the definition of the proteomic profiles in ovarian cancer would be accurate and effective in identifying which pathways are differentially altered, defining the most effective therapeutic regimen and eventually improving health outcomes.
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Received: 2 April 2013; in revised form: 23 April 2013 / Accepted: 24 April 2013 / Published: 2 May 2013
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Abstract: The special class IIb histone deacetylase, HDAC6, plays a prominent role in many cellular processes related to cancer, including oncogenesis, the cell stress response, motility, and myriad signaling pathways. Many of the lessons learned from other cancers can be applied to ovarian cancer as well. HDAC6 interacts with diverse proteins such as HSP90, cortactin, tubulin, dynein, p300, Bax, and GRK2 in both the nucleus and cytoplasm to carry out these cancerous functions. Not all pro-cancer interactions of HDAC6 involve deacetylation. The idea of using HDAC6 as a target for cancer treatment continues to expand in recent years, and more potent and specific HDAC6 inhibitors are required to effectively down-regulate the tumor-prone cell signaling pathways responsible for ovarian cancer.
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Received: 14 February 2013; in revised form: 18 April 2013 / Accepted: 24 April 2013 / Published: 7 May 2013
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Abstract: Resistin is a novel hormone that is secreted by human adipocytes and mononuclear cells and is associated with obesity, insulin resistance and inflammation. Recently, resistin has been postulated to play a role in angiogenesis. Here, we investigated the hypothesis that resistin regulates ovary carcinoma production of vascular endothelial growth factor (VEGF) and the angiogenic processes. We found that in human ovarian epithelial carcinoma cells (HO-8910), resistin (10–150 ng/mL) enhanced both VEGF protein and mRNA expression in a time- and concentration-dependent manner, as well as promoter activity. Furthermore, resistin enhanced DNA-binding activity of Sp1 with VEGF promoter in a PI3K/Akt-dependent manner. PI3K/Akt activated by resistin led to increasing interaction with Sp1, triggering a progressive phosphorylation of Sp1 on Thr453 and Thr739, resulting in the upregulation of VEGF expression. In an in vitro angiogenesis system for endothelial cells (EA.hy926) co-cultured with HO-8910 cells, we observed that the addition of resistin stimulated endothelial cell tube formation, which could be abolished by VEGF neutralizing antibody. Our findings suggest that the PI3K/Akt-Sp1 pathway is involved in resistin-induced VEGF expression in HO-8910 cells and indicates that antiangiogenesis therapy may be beneficial treatment against ovarian epithelial carcinoma, especially in obese patients.
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Received: 21 March 2013; in revised form: 26 April 2013 / Accepted: 27 April 2013 / Published: 17 May 2013
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Abstract: Claudins are a family of tight junction proteins regulating paracellular permeability and cell polarity with different patterns of expression in benign and malignant human tissues. There are approximately 27 members of the claudin family identified to date with varying cell and tissue-specific expression. Claudins-3, -4 and -7 represent the most highly differentially expressed claudins in ovarian cancer. While their exact role in ovarian tumors is still being elucidated, these proteins are thought to be critical for ovarian cancer cell invasion/dissemination and resistance to chemotherapy. Claudin-3 and claudin-4 are the natural receptors for the Clostridium perfringens enterotoxin (CPE), a potent cytolytic toxin. These surface proteins may therefore represent attractive targets for the detection and treatment of chemotherapy-resistant ovarian cancer and other aggressive solid tumors overexpressing claudin-3 and -4 using CPE-based theranostic agents.
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Received: 17 April 2013; in revised form: 9 May 2013 / Accepted: 13 May 2013 / Published: 24 May 2013
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Abstract: Objective: The aim of this study was to analyze the correlation and clinical significance between the expression of Mucin-1 (MUC1) and the Lewis y antigen with chemoresistance in ovarian epithelial cancers. Methods: Ovarian cancer patients (n = 92) treated at our hospital from May 2005 to July 2009 were divided, according to their treatment and follow-up outcomes, into a resistant group (n = 37) or sensitive group (n = 55). The expression of MUC1 and Lewis y antigen in ovarian cancer tissues was detected using immunohistochemistry and correlated with chemoresistance. Results: The positive rates of MUC1 and Lewis y antigen in the resistant group were both 91.89%, significantly higher than their positive rates in the sensitive group (65.45% and 69.09%, respectively, and both p < 0.05). MUC1 or Lewis y expression and the pathological stage of the tissue were independent risk factors for chemoresistance (all p < 0.05). Conclusion: The increased expression of MUC1 and the Lewis y antigen is a significant risk factor for chemoresistance in patients with ovarian epithelial cancer.
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Received: 23 April 2013; in revised form: 11 May 2013 / Accepted: 14 May 2013 / Published: 24 May 2013
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Abstract: Epithelial ovarian cancer (EOC) is one of the leading causes of cancer deaths in women worldwide. Ubiquitin-conjugating enzyme 9 (Ubc9), the sole conjugating enzyme for sumoylation, regulates protein function and plays an important role in sumoylation-mediated cellular pathways. Although sumoylation plays a key role in DNA repair and tumorgenesis, whether Ubc9 is involved in EOC progression remains unknown. In the present study, we constructed Ubc-9 expressed recombined plasmid pEGFP-N1-Ubc9. The mRNA levels of Ubc9 were confirmed in human ovarian cell lines before and after transfection with pEGFP-N1-Ubc9 or small interfering RNA (siRNA) targeted Ubc9 by real-time polymerase chain reaction (PCR). The MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide) assay was used to observe the effect of Ubc9 on cell proliferation. The protein levels of Ubc9, and proliferation-related signals Akt and physphorylated Akt were determined by Western blot. Our results showed that proliferation of EOC cells increased significantly in Ubc9 overexpressing cells, but decreased in Ubc9 knockdown cells. The physphorylation of Akt showed similar trends. In addition, the inhibitor of PI3K/Akt signaling pathway, LY294002, dramatically inhibited the growth of Ubc9 overexpressing cells. Therefore, Ubc9 gene plays an important role in cell proliferation in EOC through PI3K/Akt signaling pathway.
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Received: 1 March 2013; in revised form: 28 March 2013 / Accepted: 9 May 2013 / Published: 17 June 2013
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Abstract: Human chorionic gonadotropin beta subunit (CGB) is a marker of pregnancy as well as trophoblastic and nontrophoblastic tumors. CGB is encoded by a cluster of six genes, of which type II genes (CGB3/9, 5 and 8) have been shown to be upregulated in relation to type I genes (CGB6/7) in both placentas and tumors. Recent studies revealed that CGB1 and CGB2, originally considered as pseudogenes, might also be active, however, the protein products of these genes have not yet been identified. Our study demonstrates the presence of CGB1 and CGB2 transcripts in ovarian carcinomas. While CGB1 and CGB2 gene activation was not detected in normal ovaries lacking cancerous development, our study demonstrates the presence of CGB1 and CGB2 transcripts in 41% of analyzed ovarian cancer cases.
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Planned Papers
The below list represents only planned manuscripts. Some of these
manuscripts have not been received by the Editorial Office yet. Papers
submitted to MDPI journals are subject to peer-review.
Type of Paper: Review
Title: Beyond Hereditary Mutations: Alterations in the Fanconi Anemia/BRCA Pathway and its Role in Ovarian Tumorigenesis
Authors: Hays, L.E. and Pejovic, T.
Affiliation: Oregon Health & Science University, Portland, Oregon
Abstract: The Fanconi anemia (FA)/BRCA pathway consists of fifteen proteins that mediate DNA homologous recombination and promote chromosomal instability. Here we review the evidence that genetic and epigenetic alterations in BRCA2 (FANCD1), BRIP1 (FANCJ), FANCD2, FANCF, PALB2 (FANCN) and RAD51C (FANCO), render ovarian cells susceptible to malignant transformation. In addition, we discuss the paradoxical findings that BRCA2 and FANCD2 are upregulated in subsets of ovarian cancer patients and how these findings suggest potential tailored therapies.
Last update: 11 January 2013
