The hypoxia-related microRNA miR-199a-3p displays tumor suppressor functions in ovarian carcinoma

// Yasuto Kinose 1 , Kenjiro Sawada 1 , Koji Nakamura 1 , Ikuko Sawada 1 , Aska Toda 1 , Erika Nakatsuka 1 , Kae Hashimoto 1 , Seiji Mabuchi 1 , Kazuhiro Takahashi 2 , Hirohisa Kurachi 3 , Ernst Lengyel 4 and Tadashi Kimura 1 1 Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan 2 Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, Yamagata, Japan 3 Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan 4 Departments of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA Correspondence to: Kenjiro Sawada, email: // Keywords : ovarian cancer, miR-199a-3p, hypoxia, c-Met, microRNA Received : October 10, 2014 Accepted : February 21, 2014 Published : March 15, 2015 Abstract During the dissemination of ovarian cancer cells, the cells float in the peritoneal cavity without access to a vascular supply and so are exposed to hypoxic conditions, which may cause the ovarian cancer cells to acquire a more aggressive and malignant phenotype. In this study, we screened microRNAs (miRNAs) to identify those that displayed altered expression patterns under hypoxic conditions and then analyzed their functional roles in ovarian cancer progression. miRNA PCR arrays performed on cells from 2 ovarian cancer cell lines (CaOV3 and RMUG-S) revealed miR-199a-3p as one of the miRNAs that are downregulated under hypoxia. In silico analyses indicated that MET is one of the target genes for miR-199a-3p; subsequently, miR-199a-3p expression was found to be inversely correlated with c-Met expression in ovarian cancer. Transfection of precursor miR-199a-3p into ovarian cancer cells reduced c-Met expression and inhibited the phosphorylation of c-Met, extracellular signal-regulated kinase, and AKT; in addition, proliferation, adhesion, and invasiveness were inhibited. Moreover, overexpression of miR-199a-3p in cancer cells significantly suppressed peritoneal dissemination in a xenograft model. In summary, the hypoxia-related microRNA miR-199a-3p drastically inhibits ovarian cancer progression through the downregulation of c-Met expression. Therefore, miR-199a-3p is a potential target for treating ovarian cancer dissemination.