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

Publisher: Nature Publishing Group Country of Publication: England NLM ID: 8711562 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-5594 (Electronic) Linking ISSN: 09509232 NLM ISO Abbreviation: Oncogene Subsets: MEDLINE

Publication: <2002->: Basingstoke : Nature Publishing Group
Original Publication: Basingstoke, Hampshire, UK : Scientific & Medical Division, MacMillan Press, c1987-

Cell Movement* ; Gene Expression Regulation, Neoplastic* ; Tumor Microenvironment*; MicroRNAs/*genetics ; Omentum/*pathology ; Ovarian Neoplasms/*genetics ; Ovarian Neoplasms/*pathology; Animals ; Apoptosis ; Blotting, Western ; Cell Adhesion ; Cell Proliferation ; Female ; Humans ; Immunoenzyme Techniques ; Mice ; Mice, Nude ; Omentum/metabolism ; Ovarian Neoplasms/metabolism ; RNA, Messenger/genetics ; Real-Time Polymerase Chain Reaction ; Reverse Transcriptase Polymerase Chain Reaction ; Tumor Cells, Cultured ; Urokinase-Type Plasminogen Activator/genetics ; Urokinase-Type Plasminogen Activator/metabolism ; Xenograft Model Antitumor Assays

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.

Epigenetics. 2012 Mar;7(3):216-24. (PMID: 22430797)
Genes Cancer. 2011 Feb;2(2):140-50. (PMID: 21779487)
J Clin Invest. 2013 Nov;123(11):4612-26. (PMID: 24216476)
Cancer Res. 2008 Apr 1;68(7):2329-39. (PMID: 18381440)
Am J Pathol. 2010 Sep;177(3):1053-64. (PMID: 20651229)
J Clin Invest. 2014 Oct;124(10):4614-28. (PMID: 25202979)
Cell. 2011 Oct 14;147(2):275-92. (PMID: 22000009)
Nat Rev Cancer. 2002 Aug;2(8):563-72. (PMID: 12154349)
Annu Rev Biochem. 2005;74:481-514. (PMID: 15952895)
Nat Med. 2011;17(11):1498-503. (PMID: 22037646)
Nature. 2007 Oct 11;449(7163):682-8. (PMID: 17898713)
Gynecol Oncol. 2009 Aug;114(2):265-72. (PMID: 19450871)
Cell. 2014 Feb 27;156(5):1002-16. (PMID: 24581498)
Biochim Biophys Acta. 2013 Oct;1831(10):1533-41. (PMID: 23500888)
Nature. 2012 Feb 16;482(7385):347-55. (PMID: 22337054)
Nat Cell Biol. 2013 Jun;15(6):546-54. (PMID: 23728460)
Eur J Cancer. 2010 Oct;46(15):2828-36. (PMID: 20655737)
Proc Natl Acad Sci U S A. 2008 May 13;105(19):7004-9. (PMID: 18458333)
Cancer Discov. 2012 Dec;2(12):1100-8. (PMID: 23171795)
Oncol Rep. 2013 Feb;29(2):637-45. (PMID: 23174953)
Oncogene. 2013 May 2;32(18):2282-91, 2291.e1-7. (PMID: 22797075)
Nat Cell Biol. 2008 Feb;10(2):202-10. (PMID: 18193036)
Oncogene. 2009 Nov 5;28(44):3937-48. (PMID: 19701247)
Curr Pharm Des. 2004;10(1):39-49. (PMID: 14754404)
Adv Drug Deliv Rev. 2014 Dec 15;79-80:184-92. (PMID: 25034878)
Clin Cancer Res. 2001 Jun;7(6):1743-9. (PMID: 11410515)
Int J Cancer. 2010 Sep 1;127(6):1363-72. (PMID: 20073067)
Cell. 2009 Jun 12;137(6):1032-46. (PMID: 19524507)
Oncogene. 2011 Mar 31;30(13):1566-76. (PMID: 21119598)
Int J Cancer. 2007 Oct 1;121(7):1463-72. (PMID: 17546601)
Nat Rev Mol Cell Biol. 2013 Aug;14(8):475-88. (PMID: 23800994)
Cancer Discov. 2011 Jul;1(2):144-57. (PMID: 22303516)
Exp Cell Res. 1985 Oct;160(2):499-513. (PMID: 3899694)
Clin Cancer Res. 2001 Aug;7(8):2396-404. (PMID: 11489818)
J Cell Sci. 2008 Nov 15;121(Pt 22):3747-56. (PMID: 18940913)
Cell. 2013 Jul 18;154(2):311-24. (PMID: 23830207)
Clin Cancer Res. 1997 Nov;3(11):2017-24. (PMID: 9815592)
Nat Rev Cancer. 2009 Jun;9(6):415-28. (PMID: 19461667)
J Clin Invest. 2013 Feb;123(2):566-79. (PMID: 23321667)
Gynecol Oncol. 2001 Aug;82(2):299-304. (PMID: 11531283)
Mol Cancer Ther. 2013 Dec;12(12):2628-39. (PMID: 24061648)
Leuk Res. 2011 Sep;35(9):1226-32. (PMID: 21724256)
Cancer Cell. 2012 Mar 20;21(3):309-22. (PMID: 22439926)
Nat Rev Cancer. 2011 Oct;11(10):719-25. (PMID: 21941283)
Nature. 2010 Apr 22;464(7292):1196-200. (PMID: 20364122)
PLoS One. 2013;8(4):e61658. (PMID: 23613894)

R01 CA111882 United States CA NCI NIH HHS; R01 CA169604 United States CA NCI NIH HHS; R21 NS075702 United States NS NINDS NIH HHS

0 (MIRN193 microRNA, human)
0 (MicroRNAs)
0 (RNA, Messenger)
EC 3.4.21.73 (Urokinase-Type Plasminogen Activator)

Date Created: 20150324 Date Completed: 20160308 Latest Revision: 20181113

20240829

PMC4580483

10.1038/onc.2015.43

25798837