Abstract
Abstract MicroRNAs (miRNAs), a class of small non-coding RNAs, play important roles in cancer development by perturbing the expression of target genes. DNA methylation, a well-studied epigenetic event, also influences gene expression and aberrant methylation is frequently observed in cancer. We previously reported a new paradigm in which hypermethylation-mediated silencing of a miRNA de-repressed its oncogenic target in cancer cells. SOX4, an oncogene, was found to be overexpressed in endometrial cancer, partly because of hypermethylation of miR-129-2. Herein, thirteen additional miRNAs targeting on the 3′-end of untranslated regions of SOX4, and encompassing CpG islands, were identified using computational analysis. Hypermethylation of eight of the thirteen miRNAs was detected in at least two of seven endometrial cancer cell lines. miR-203 was selected for further analysis because this locus was predominantly hypermethylated in endometrial cancer cell lines, but not in normal endometrium. miR-203 expression can be reactivated by pharmacologic induction of DNA demethylation and histone acetylation, indicating that the loss of miR-203 expression is associated with promoter hypermethylation in endometrial cancer. Restoration of miR-203 by cell transfection decreased SOX4 expression and reduced proliferation of endometrial cancer cells. To confirm these in vitro findings in primary endometrial tumors, specimens from two cohorts were analyzed for miR-203 methylation by quantitative pyrosequencing or MassARRAY. In one cohort, miR-203 was significantly hypermethylated in endometrial tumors (n=31), but not in adjacent or un-related normal (n=18) specimens. Methylation of this locus is related to lymphatic and vascular invasion. In the other cohort, increased methylation was observed in primary tumors (n=114), but not in normal controls (n=22). Hypermethylation of miR-203 was positively associated with MLH1 methylation and MSI status. In conclusion, we present an emerging phenomenon that epigenetic silencing of multiple miRNAs could lead to overexpression of a single oncogene in endometrial cancer. This work is supported, in part, by NIH grants U54 CA113001 (THH) and P50 CA134254 (PJG, THH). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4040. doi:1538-7445.AM2012-4040
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