title: 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. 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.
authors: Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA.|Medical Sciences Program, Indiana University School of Medicine, Indiana University, Bloomington, IN, USA.
authors: A K
authors: AK
authors: Mitra
authors: Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA.
authors: C Y
authors: CY
authors: Chiang
authors: Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA.
authors: P
authors: P
authors: Tiwari
authors: Medical Sciences Program, Indiana University School of Medicine, Indiana University, Bloomington, IN, USA.
authors: S
authors: S
authors: Tomar
authors: Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA.
authors: K M
authors: KM
authors: Watters
authors: Division of Hematology/Oncology, Northwestern University, Feinberg School of Medicine, Chicago, IL, USA.
authors: M E
authors: ME
authors: Peter
authors: Department of Obstetrics and Gynecology, Section of Gynecologic Oncology - Center for Integrative Science, University of Chicago, Chicago, IL, USA.
authors: E
authors: E
authors: Lengyel
mesh_terms: D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007124:Immunoenzyme Techniques; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D009852:Omentum / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: C546818:MIRN193 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D014568:Urokinase-Type Plasminogen Activator