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

A. K. Mitra, C. Y. Chiang, P. Tiwari, S. Tomar, K. M. Watters, M. E. Peter, E. Lengyel

Research output: Contribution to journalArticle

44 Scopus citations

Abstract

The cross-talk between ovarian cancer (OvCa) cells and the metastatic microenvironment is an essential determinant of successful colonization. MicroRNAs (miRNAs) have 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 three-dimensional 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-mediated decrease in the expression of miR-193b in the cancer cells. 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, a known tumor-associated protease. These findings link paracrine signals from the microenvironment to the regulation of a key miRNA in cancer cells. Targeting miR-193b, which is essential for metastatic colonization of cancer cells could prove effective in the treatment of OvCa metastasis.

Original languageEnglish (US)
Pages (from-to)5923-5932
Number of pages10
JournalOncogene
Volume34
Issue number48
DOIs
StatePublished - Nov 26 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Mitra, A. K., Chiang, C. Y., Tiwari, P., Tomar, S., Watters, K. M., Peter, M. E., & Lengyel, E. (2015). Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. Oncogene, 34(48), 5923-5932. https://doi.org/10.1038/onc.2015.43