title: RFX-1-dependent activation of SHP-1 inhibits STAT3 signaling in hepatocellular carcinoma cells.
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.
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.affiliation: Transplant Medicine & Surgery Research Centre, Department of Surgery, Changhua Christian Hospital, Changhua City, Changhua County 500, Taiwan.
authors.forename: Heng-Chieh
authors.initials: HC
authors.lastname: Chiang
authors.affiliation: Institute of Biochemistry and Molecular Biology, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Ping-Hui
authors.initials: PH
authors.lastname: Tseng
authors.affiliation: Department of Medical Research and National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Hsu
authors.affiliation: Department of Medical Research and National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei 100, Taiwan.
authors.forename: Yong-Shi
authors.initials: YS
authors.lastname: Li
authors.affiliation: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu 310, Taiwan.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu 310, Taiwan.
authors.forename: Ching-Huai
authors.initials: CH
authors.lastname: Ko
authors.affiliation: Biomedical Technology and Device Research Labs, Industrial Technology Research Institute, Hsinchu 310, Taiwan.
authors.forename: Mai-Wei
authors.initials: MW
authors.lastname: Lin
authors.affiliation: Department of Pathology, St Martin De Porres Hospital, Chiayi 600, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei 112, Taiwan and National Yang-Ming University School of Medicine, Taipei 112, Taiwan.
authors.forename: Chun-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Medical Research and National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei 100, Taiwan, kfchen1970@ntu.edu.tw.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei 112, Taiwan, kfchen1970@ntu.edu.tw cwshiau@ym.edu.tw.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D047369:Chromatin Immunoprecipitation; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D007124:Immunoenzyme Techniques; D008113:Liver Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D008156:Luciferases / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D011401:Promoter Regions, Genetic / Q000235:genetics; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000235:genetics* / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D014157:Transcription Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D010671:Phenylurea Compounds; D011758:Pyrroles; C000605537:RFX1 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D000071701:Regulatory Factor X Transcription Factors; D000071716:Regulatory Factor X1; C000605538:Rfx1 protein, mouse; C572884:SC-2001; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D014157:Transcription Factors; D009536:Niacinamide; D000077157:Sorafenib; D008156:Luciferases; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6