MicroRNA Signatures in Human Ovarian Cancer

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 miR200b, 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. [Cancer Res 2007;67(18):8699-707]

Potentially important microRNA cluster on chromosome 17p13.1 in primary peritoneal carcinoma

“…Importantly, our results do not preclude a common site of origin; they probably reflect temporal 19 described DNA copy number alterations at all genomic loci for our selected microRNAs in ovarian serous carcinoma. In the study by Iorio et al, 9 miR181a and miR-195 were downregulated in ovarian serous carcinoma, whereas Nam et al 52 demonstrate differential expression of miR-16. Yang et al 14 did not describe dysregulation of any of our selected microRNAs, however their group used microRNA microarrays (which are less sensitive and have a smaller dynamic range in comparison to PCR) to generate pilot data.…”

“…64 Recent research suggests that DNA methylation may also be involved in the regulation of microRNA expression in ovarian cancer, and the methylation can be reversed by DNA methyltransferase inhibitors. 9,65 Indeed, microRNA control and deregulation may be more complex as widespread microRNA repression by transcription factors such as c-myc (that targets miR-195/miR-497) have also been found to contribute to tumourigenesis. 66 Our data demonstrate decreased p53 expression in primary peritoneal carcinoma relative to ovarian serous carcinoma.…”

“…They have been found to have roles in cell growth, differentiation, apoptosis and tumourigenesis. [7][8][9][10][11][12][13][14] Furthermore, unique microRNA expression profiles have been able to classify various cancers. Recently, microRNAs were implicated in the development of ovarian cancer: 39 microRNAs are differentially regulated between tumour and normal ovarian tissue.…”

“…Recently, microRNAs were implicated in the development of ovarian cancer: 39 microRNAs are differentially regulated between tumour and normal ovarian tissue. 9 MicroRNA production involves cleavage of a long nascent transcript (primary microRNA) to form a 70-100 nucleotide hairpin precursor (precursor microRNA), which is in turn processed to form a microRNA duplex. One strand of this duplex is incorporated into the RISC complex where it will bind through partial sequence homology to the 3 0 UTR of target mRNAs causing their translational repression.…”

miR-205 is frequently downregulated in prostate cancer and acts as a tumor suppressor by inhibiting tumor growth

“…DISCUSSION miRNAs are a class of small RNAs that regulate various physiological and pathological mechanisms. 18 Although upregulated in ovarian, bladder and breast carcinomas, [19][20][21] miR-205 has been reported to be downregulated in oesophageal cancers. 22 Thus, miR-205 might act as a doubled-edged sword by targeting opposite functional genes, as one miRNA can target a dozen mRNAs, impacting many molecules …”