RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells

Jung Chen Su, Heng Chieh Chiang, Ping Hui Tseng, Wei Tien Tai, Cheng Yi Hsu, Yong Shi Li, Jui Wen Huang, Ching Huai Ko, Mai Wei Lin, Pei Yi Chu, Chun Yu Liu, Kuen Feng Chen, Chung Wai Shiau

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

Abstract

Regulatory factor X-1 (RFX-1) is a transcription factor that has been linked to negative regulation of tumor progression; however, its biological function and signaling cascades are unknown. Here, we performed several studies to elucidate the roles of RFX-1 in the regulation of SHP-1 in hepatocellular carcinoma (HCC) cells. Overexpression of RFX-1 resulted in the activation of SHP-1 and repressed colony formation of HCC cells. In addition, by a mouse xenograft model, we demonstrated that RFX-1 overexpression also inhibited the tumor growth of HCC cells in vivo, suggesting that RFX-1 is of potential interest for small-molecule-targeted therapy. We also found that SC-2001, a bipyrrole molecule, induced apoptosis in HCC cells through activating RFX-1 expression. SC-2001 induced RFX-1 translocation from the cytosol to nucleus, bound to the SHP-1 promoter, and activated SHP-1 transcription. In a xenograft model, knockdown of RFX-1 reversed the antitumor effect of SC-2001. Notably, SC-2001 is much more potent than sorafenib, a clinically approved drug for HCC, in in vitro and in vivo assays. Our study confirmed that RFX-1 acts as a tumor suppressor in HCC and might be a new target for HCC therapy. The findings of this study also provide a new lead compound for targeted therapy via the activation of the RFX-1/SHP-1 pathway.

Original languageEnglish
Pages (from-to)2807-2814
Number of pages8
JournalCarcinogenesis
Volume35
Issue number12
DOIs
StatePublished - 1 Dec 2014

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