The STAT3-miRNA-92-Wnt signaling pathway regulates spheroid formation and malignant progression in ovarian cancer

Min Wei Chen, Shu Ting Yang, Ming Hsien Chien, Kuo Tai Hua, Chin Jui Wu, S. M. Hsiao, Hao Lin, Michael Hsiao, Jen Liang Su, Lin Hung Wei

Research output: Contribution to journalArticle

52 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1955-1967
Number of pages13
JournalCancer Research
Volume77
Issue number8
DOIs
Publication statusPublished - Apr 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Chen, M. W., Yang, S. T., Chien, M. H., Hua, K. T., Wu, C. J., Hsiao, S. M., Lin, H., Hsiao, M., Su, J. L., & Wei, L. H. (2017). The STAT3-miRNA-92-Wnt signaling pathway regulates spheroid formation and malignant progression in ovarian cancer. Cancer Research, 77(8), 1955-1967. https://doi.org/10.1158/0008-5472.CAN-16-1115