|Title:||The STAT3-miRNA-92-Wnt signaling pathway regulates spheroid formation and malignant progression in ovarian cancer||Authors:||Chen M.-W.
|Issue Date:||2017||Journal Volume:||77||Journal Issue:||8||Start page/Pages:||1955-1967||Source:||Cancer Research||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. ? 2017 American Association for Cancer Research.
|URI:||https://scholars.lib.ntu.edu.tw/handle/123456789/458216||ISSN:||0008-5472||DOI:||10.1158/0008-5472.CAN-16-1115||SDG/Keyword:||beta catenin; dickkopf 1 protein; microRNA; microRNA 92; microRNA 92a; paclitaxel; STAT3 protein; unclassified drug; Wnt protein; beta catenin; CTNNB1 protein, human; DKK1 protein, human; microRNA; MIRN92 microRNA, human; signal peptide; STAT3 protein; STAT3 protein, human; animal experiment; animal model; Article; cancer stem cell; carcinogenicity; case report; cell self-renewal; controlled study; DKK1 gene; drug resistance; female; gene disruption; human; human cell; human tissue; malignant transformation; mouse; nonhuman; ovarian cancer cell line; ovary cancer; protein targeting; signal transduction; survival; tumor seeding; tumor spheroid; upregulation; Wnt signaling pathway; animal; disease course; down regulation; genetic transcription; genetics; metabolism; multicellular spheroid; neoplasm; nonobese diabetic mouse; ovary tumor; pathology; phosphorylation; SCID mouse; tumor cell culture; xenograft; Animals; beta Catenin; Disease Progression; Down-Regulation; Drug Resistance, Neoplasm; Female; Heterografts; Humans; Intercellular Signaling Peptides and Proteins; Mice; Mice, Inbred NOD; Mice, SCID; MicroRNAs; Neoplasms, Glandular and Epithelial; Ovarian Neoplasms; Phosphorylation; Spheroids, Cellular; STAT3 Transcription Factor; Transcription, Genetic; Tumor Cells, Cultured; Wnt Signaling Pathway
|Appears in Collections:||醫學系|
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