Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis.

Abstract

The cross-talk between ovarian cancer (OvCa) cells and the metastatic microenvironment is an essential determinant of successful colonization. Micro(mi)RNAs play several critical roles during metastasis; however, the role of microenvironmental cues in the regulation of miRNAs in metastasizing cancer cells has not been studied. Using a 3D culture model that mimics the human omentum, one of the principal sites of OvCa metastasis, we identified and characterized the microenvironment-induced downregulation of a tumor suppressor miRNA, miR-193b, in metastasizing OvCa cells. The direct interaction of the OvCa cells with mesothelial cells, which cover the surface of the omentum, caused a DNA methyltransferase 1 (DNMT1) mediated decrease in the expression of miR-193b. The reduction in miR-193b enabled the metastasizing cancer cells to invade and proliferate into human omental pieces ex vivo and into the omentum of a mouse xenograft model of OvCa metastasis. The functional effects of miR-193b were mediated, in large part, by the concomitant increased expression of its target, urokinase-type plasminogen activator (uPA), a known tumor-associated protease. These findings link paracrine signals from the microenvironment with the regulation of a key miRNA that is essential for the initial steps of OvCa metastatic colonization. Targeting miR-193b could prove effective in the treatment of OvCa metastasis.