Abstract
Epithelial ovarian cancer (EOC) is the sixth most common cancer in women worldwide and, despite advances in detection and therapies, it still represents the most lethal gynecologic malignancy in the industrialized countries. Unfortunately, still relatively little is known about the molecular events that lead to the development of this highly aggressive disease. The relatively recent discovery of microRNAs (miRNA), a class of small noncoding RNAs targeting multiple mRNAs and triggering translation repression and/or RNA degradation, has revealed the existence of a new level of gene expression regulation. Multiple studies involving various types of human cancers proved that miRNAs have a causal role in tumorigenesis. Here we show that, in comparison to normal ovary, miRNAs are aberrantly expressed in human ovarian cancer. The overall miRNA expression could clearly separate normal versus cancer tissues. The most significantly overexpressed miRNAs were miR-200a, miR-141, miR-200c, and miR-200b, whereas miR-199a, miR-140, miR-145, and miR-125b1 were among the most down-modulated miRNAs. We could also identify miRNAs whose expression was correlated with specific ovarian cancer biopathologic features, such as histotype, lymphovascular and organ invasion, and involvement of ovarian surface. Moreover, the levels of miR-21, miR-203, and miR-205, up-modulated in ovarian carcinomas compared with normal tissues, were significantly increased after 5-aza-2'-deoxycytidine demethylating treatment of OVCAR3 cells, suggesting that the DNA hypomethylation could be the mechanism responsible for their overexpression. Our results indicate that miRNAs might play a role in the pathogenesis of human EOC and identify altered miRNA gene methylation as a possible epigenetic mechanism involved in their aberrant expression.
Highlights
Epithelial ovarian cancer (EOC) is the most common gynecologic malignancy and the sixth most common cancer in women worldwide, with highly aggressive natural history causing almost 125,000 deaths yearly [1]
The ovarian cancer cell line IGROV1 was originally derived by Dr Bernard (Institute Gustave Roussy, Villejuf, France), from a moderately differentiated ovarian carcinoma of an untreated patient; OAW-42 was from Dr Ulrich U. (Department of Obstetrics and Gynaecology, University of Ulm, Ulm, Germany), whereas OVCAR3, OVCAR8, and SKOV3 were purchased from the American Type Culture Collection
Using the DianaTarbase,6 we looked for confirmed targets of some of the most significant miRNAs resulting from our analyses, finding some interesting data: ERBB2 and ERBB3 receptors, for example, are targeted by miR-125 [32]; miR101, down-modulated in ovarian carcinoma, has been shown targeting the oncogene MYCN [33]
Summary
Epithelial ovarian cancer (EOC) is the most common gynecologic malignancy and the sixth most common cancer in women worldwide, with highly aggressive natural history causing almost 125,000 deaths yearly [1]. Doi:10.1158/0008-5472.CAN-07-1936 ovarian cancer survive 5 years after initial diagnosis [2]. The high mortality of this disease is mainly due to late-stage diagnosis for >70% of ovarian cancers. When ovarian cancer is diagnosed in its early stage, that is still organ confined, the 5-year survival rate exceeds 90%. Only 19% of all ovarian cancers are diagnosed at this early stage. This rather poor prognosis is due to (a) the insidious asymptomatic nature of this disease in its early onset, (b) the lack of robust and minimally invasive methods for early detection, and (c) tumor resistance to chemotherapy. The vast majority of human ovarian carcinomas are represented by ovarian epithelial cancers (OEC), deriving from the ovarian surface epithelium [3]
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