title: The hypoxia-related microRNA miR-199a-3p displays tumor suppressor functions in ovarian carcinoma.
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.
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Yasuto
authors.initials: Y
authors.lastname: Kinose
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kenjiro
authors.initials: K
authors.lastname: Sawada
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Nakamura
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Ikuko
authors.initials: I
authors.lastname: Sawada
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Aska
authors.initials: A
authors.lastname: Toda
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Erika
authors.initials: E
authors.lastname: Nakatsuka
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Kae
authors.initials: K
authors.lastname: Hashimoto
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Seiji
authors.initials: S
authors.lastname: Mabuchi
authors.affiliation: Department of Obstetrics and Gynecology, Yamagata University Faculty of Medicine, Yamagata, Japan.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Takahashi
authors.affiliation: Osaka Medical Center and Research Institute for Maternal and Child Health, Izumi, Osaka, Japan.
authors.forename: Hirohisa
authors.initials: H
authors.lastname: Kurachi
authors.affiliation: Departments of Obstetrics and Gynecology/Section of Gynecologic Oncology, University of Chicago, Chicago, IL, USA.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine, Suita, Osaka, Japan.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kimura
mesh_terms: D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002448:Cell Adhesion; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism; D000067492:RNAi Therapeutics; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D023041:Xenograft Model Antitumor Assays
chemical_list: D035683:MicroRNAs; C531408:mirn199 microRNA, human; D019859:Proto-Oncogene Proteins c-met; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: c-Met; hypoxia; miR-199a-3p; microRNA; ovarian cancer
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