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

Oncogene volume 34, pages 5923–5932 (2015)Cite this article

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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.

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Acknowledgements

We want to thank Dr AF Haney for collecting omental biopsies, Dr Abir Mukherjee for helpful discussions and G Isenberg for carefully editing the manuscript (all at the University of Chicago, Department of Obstetrics and Gynecology). We are indebted to all the patients, resident and attending physicians in the Department of Obstetrics and Gynecology at the University of Chicago for their participation in tissue collection for these experiments. This research was supported by a Marsha Rivkin Pilot Award (AKM) and by National Cancer Institute R01 CA111882 and RO1 CA169604 grants (EL) and an Ovarian Cancer Research Fund Program Project Development Grant (EL, MEP).

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Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Section of Gynecologic Oncology – Center for Integrative Science, University of Chicago, Chicago, IL, USA

    A K Mitra, C Y Chiang, P Tiwari, K M Watters & E Lengyel

  2. Medical Sciences Program, Indiana University School of Medicine, Indiana University, Bloomington, IN, USA

    A K Mitra & S Tomar

  3. Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA

    M E Peter

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  1. A K Mitra
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Correspondence to A K Mitra or E Lengyel.

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Mitra, A., Chiang, C., Tiwari, P. et al. Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. Oncogene 34, 5923–5932 (2015). https://doi.org/10.1038/onc.2015.43

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