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

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

Research output: Contribution to journalArticle

41 Citations (Scopus)

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

Fingerprint

Ovarian Neoplasms
Down-Regulation
Neoplasm Metastasis
MicroRNAs
Omentum
Neoplasms
Cellular Microenvironment
Drive
Urokinase-Type Plasminogen Activator
Methyltransferases
Heterografts
Cues
Peptide Hydrolases
DNA

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Mitra, A., 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

Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. / Mitra, Anirban; Chiang, C. Y.; Tiwari, P.; Tomar, S.; Watters, K. M.; Peter, M. E.; Lengyel, E.

In: Oncogene, Vol. 34, No. 48, 26.11.2015, p. 5923-5932.

Research output: Contribution to journalArticle

Mitra, A, Chiang, CY, Tiwari, P, Tomar, S, Watters, KM, Peter, ME & Lengyel, E 2015, 'Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis', Oncogene, vol. 34, no. 48, pp. 5923-5932. https://doi.org/10.1038/onc.2015.43
Mitra A, Chiang CY, Tiwari P, Tomar S, Watters KM, Peter ME et al. Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. Oncogene. 2015 Nov 26;34(48):5923-5932. https://doi.org/10.1038/onc.2015.43
Mitra, Anirban ; Chiang, C. Y. ; Tiwari, P. ; Tomar, S. ; Watters, K. M. ; Peter, M. E. ; Lengyel, E. / Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. In: Oncogene. 2015 ; Vol. 34, No. 48. pp. 5923-5932.
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