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Supplementary information from The STAT3-miRNA-92-Wnt Signaling Pathway Regulates Spheroid Formation and Malignant Progression in Ovarian Cancer

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posted on 2023-03-31, 01:04 authored by 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

Table S1. Target sequence of STAT3 shRNAs Table S2. Primers sequence of miR-92a and pre-miR-92a QPCR Table S3, Clinicopathologic characteristics of patients with epithelial ovarian cancer Fig.S1. STAT3 silencing by shRNA in EOC cell lines inhibits the cell viability in 3-dimensional cultures. Fig.S2. Immunoblot analysis of SKOV3/SKOV3 STAT3-KD cells for the expression of cleaved-PARP, Bcl-xL, and xIAP. b-actin was used as a loading control. Fig.S3. Top, representative spheroids formed by ES2 scramble/ES2 STAT3-KD cells treated with or without paclitaxel (PTX). Bottom, plot of the number of spheroids formed per 1000 cells in selected cells. Error bars represent the SD from triplicate cultures.

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ARTICLE 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.

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