title: The STAT3-miRNA-92-Wnt Signaling Pathway Regulates Spheroid Formation and Malignant Progression in Ovarian Cancer.
abstract: Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell-like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected Wnt/β-catenin signaling via the miR-92a/DKK1-regulatory pathways. Targeting STAT3 in combination with paclitaxel synergistically reduced peritoneal seeding and prolonged survival in a murine model of intraperitoneal ovarian cancer. Overall, our findings define a STAT3-miR-92a-DKK1 pathway in the generation of cancer stem-like cells in ovarian tumors, with potential therapeutic applications in blocking their progression.Cancer Res; 77(8); 1955-67. ©2017 AACR.
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Min-Wei
authors.initials: MW
authors.lastname: Chen
authors.affiliation: National Institute of Cancer Research, National Health Research Institute, Zhunan, Miaoli County, Taiwan.
authors.forename: Shu-Ting
authors.initials: ST
authors.lastname: Yang
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ming-Hsien
authors.initials: MH
authors.lastname: Chien
authors.affiliation: Graduate Institute of Toxicology, College of Medicine, National Taiwan University, Taipei, Taiwan.
authors.forename: Kuo-Tai
authors.initials: KT
authors.lastname: Hua
authors.affiliation: Department of Obstetrics & Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Chin-Jui
authors.initials: CJ
authors.lastname: Wu
authors.affiliation: Department of Obstetrics and Gynecology, Far Eastern Memorial Hospital, New Taipei, Taiwan.
authors.forename: S M
authors.initials: SM
authors.lastname: Hsiao
authors.affiliation: Department of Obstetrics and Gynecology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan.
authors.forename: Hao
authors.initials: H
authors.lastname: Lin
authors.affiliation: Medical Biology, Genomics Research Center, Academia Sinica, Taipei, Taiwan.
authors.forename: Michael
authors.initials: M
authors.lastname: Hsiao
authors.affiliation: National Institute of Cancer Research, National Health Research Institute, Zhunan, Miaoli County, Taiwan. weilh1966@gmail.com jlsu@nhri.org.tw.|Graduate Institute of Cancer Biology, China Medical University, Taichung, Taiwan.|Department of Biotechnology, Asia University, Taichung, Taiwan.|Center for Molecular Medicine, China Medical University Hospital, Taichung, Taiwan.
authors.forename: Jen-Liang
authors.initials: JL
authors.lastname: Su
authors.affiliation: Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan. weilh1966@gmail.com jlsu@nhri.org.tw.|Department of Obstetrics & Gynecology, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Lin-Hung
authors.initials: LH
authors.lastname: Wei
mesh_terms: D000818:Animals; D000077216:Carcinoma, Ovarian Epithelial; D018450:Disease Progression; D015536:Down-Regulation; D019008:Drug Resistance, Neoplasm; D005260:Female; D064593:Heterografts; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009375:Neoplasms, Glandular and Epithelial / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D018874:Spheroids, Cellular; D014158:Transcription, Genetic; D014407:Tumor Cells, Cultured; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; C501126:DKK1 protein, human; D036341:Intercellular Signaling Peptides and Proteins; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051176:beta Catenin