Epigenetic Repression of microRNA-129-2 Leads to Overexpression of SOX4 Oncogene in Endometrial Cancer

摘要

Genetic amplification, mutation, and translocation are known to play a causal role in the up-regulation of an oncogene in cancer cells. Here we report an emerging role of microRNA, the epigenetic deregulation of which may also lead to this oncogenic activation. SOX4, an oncogene belonging to the SRY-related high-mobility-group-box family, was found to be over-expressed (P<0.005) in endometrial tumors (n=74) compared with uninvolved controls (n=20). This gene is computationally predicted to be the target of a microRNA, miR-129-2. When compared to the matched endometria, the expression of miR-129-2 was lost in 27 of 31 primary endometrial tumors that also showed a concomitant gain of SOX4 expression (P<0.001). This inverse relationship is associated with hypermethylation of the miR-129-2 CpG island, which was observed in endometrial cancer cell lines (n=6) and 68% of 117 endometrioid endometrial tumors analyzed. Reactivation of miR-129-2 in cancer cells by pharmacological induction of histone acetylation and DNA demethylation resulted in decreased SOX4 expression. In addition, restoration of miR-129-2 by cell transfection led to decreased SOX4 expression and reduced proliferation of cancer cells. Further analysis found a significant correlation of hypermethylated miR-129-2 with microsatellite instability and MLH1 methylation status (P<0.001), and poor overall survival (P<0.039) in patients. Therefore, these results imply that the aberrant expression of SOX4 is, in part, caused by epigenetic repression of miR-129-2 in endometrial cancer. Unlike the notion that promoter hypomethylation may up-regulate an oncogene, we present a new paradigm in which hypermethylation-mediated silencing of a microRNA de-represses its oncogenic target in cancer cells.