title: The miR-200 family differentially regulates sensitivity to paclitaxel and carboplatin in human ovarian carcinoma OVCAR-3 and MES-OV cells.
abstract: We studied the role of miRNA-200 family members in cellular sensitivity to paclitaxel and carboplatin, using two ovarian cancer cell lines, OVCAR-3 and MES-OV, and their paclitaxel resistant variants OVCAR-3/TP and MES-OV/TP. Both resistant variants display a strong epithelial-mesenchymal transition (EMT) phenotype, with marked decreases in expression of miR-200c and miR-141 in OVCAR-3/TP, and down-regulation of all five members of the miR-200 family in MES-OV/TP. Lentiviral transfection of inhibitors of miR-200c or miR-141 in parental OVCAR-3 triggered EMT and rendered the cells resistant to paclitaxel and carboplatin. Conversely, the infection of OVCAR-3/TP cells with retroviral particles carrying the miR-200ab429 and 200c141 clusters triggered a partial mesenchymal to epithelial transition (MET). This partial MET was not sufficient to re-sensitize OVCAR-3/TP cells to paclitaxel. However, the miR-200c/miR-141 cluster transfectants became 6-8x resistant to carboplatin, an unexpected result, whereas miR-200a/miR-200b/miR-429 had no effect. Transfecting the OVCAR-3/TP GFP cells with specific miRNA mimics confirmed these data. MiR-200c and miR-141 mimics conferred resistance to carboplatin in MES-OV/TP cells, similar to OVCAR-3/TP, but sensitized MES-OV to paclitaxel. Several genes involved in balancing oxidative stress were altered in OVCAR-3/TP 200c141 cells compared to controls. The miR-200 family plays major, cell-context dependent roles in regulating EMT and sensitivity to carboplatin and paclitaxel in OVCAR-3 and MES-OV cells.
authors.affiliation: Stanford University School of Medicine, Oncology Division, Stanford, CA 94305, USA.
authors.forename: Anamaria
authors.initials: A
authors.lastname: Brozovic
authors.affiliation: Stanford University School of Medicine, Oncology Division, Stanford, CA 94305, USA.
authors.forename: George E
authors.initials: GE
authors.lastname: Duran
authors.affiliation: Stanford University School of Medicine, Oncology Division, Stanford, CA 94305, USA.
authors.forename: Yan C
authors.initials: YC
authors.lastname: Wang
authors.affiliation: Stanford University School of Medicine, Oncology Division, Stanford, CA 94305, USA.
authors.forename: E Brian
authors.initials: EB
authors.lastname: Francisco
authors.affiliation: Stanford University School of Medicine, Oncology Division, Stanford, CA 94305, USA. Electronic address: brandy@stanford.edu.
authors.forename: Branimir I
authors.initials: BI
authors.lastname: Sikic
mesh_terms: D016190:Carboplatin / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D035683:MicroRNAs / Q000235:genetics / Q000502:physiology*; D005810:Multigene Family; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D017239:Paclitaxel / Q000627:therapeutic use*
chemical_list: C533896:MIRN200 microRNA, human; D035683:MicroRNAs; D016190:Carboplatin; D017239:Paclitaxel
keywords: Carboplatin; Drug resistance; Epithelial mesenchymal transition; Paclitaxel; miRNA-200