title: STAT3 mediates regorafenib-induced apoptosis in hepatocellular carcinoma.
abstract: OBJECTIVE
  Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC).
  
  
  METHODS
  HCC cell lines (PLC5, HepG2, Hep3B, SK-Hep1, and HA59T) were used to investigate the in vitro effect of regorafenib. Phosphatase activity was analyzed in HCC cells and purified SHP-1 proteins. PLC5-bearing mice were used to test the therapeutic efficiency of 20 and 40 mg/kg/d treatment with regorafenib ([Formula: see text] mice). The clinical relevance of STAT3 signaling was investigated with 142 tumor samples from different patients with HCC. Descriptive statistical analysis was used to compare the baseline characteristics of patients and the expression of p-STAT3.
  
  
  RESULTS
  Regorafenib inhibited STAT3-related signaling in a dose-dependent manner and was a more potent inhibitor of STAT3 than sorafenib. Regorafenib increased SHP-1 phosphatase activity in purified SHP-1 protein directly. N-SH2 domain deletion and D61A mutants mimicking open-form SHP-1 partially abolished regorafenib-induced STAT3 inhibition and apoptosis. Importantly, a higher level of expression of STAT3 was found in patients with advanced clinical stages (P = 0.009) and poorly differentiated tumors (P = 0.035).
  
  
  CONCLUSIONS
  Regorafenib induced significant tumor inhibition by relieving the autoinhibited N-SH2 domain of SHP-1 directly and inhibiting p-STAT3 signals. STAT3 may be suitable as a prognostic marker of HCC development, and may be a druggable target for HCC-targeted therapy using regorafenib.
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Wei-Tien
authors.initials: WT
authors.lastname: Tai
authors.affiliation: Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan. School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
authors.forename: Pei-Yi
authors.initials: PY
authors.lastname: Chu
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Chung-Wai
authors.initials: CW
authors.lastname: Shiau
authors.affiliation: Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Yao-Li
authors.initials: YL
authors.lastname: Chen
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Yong-Shi
authors.initials: YS
authors.lastname: Li
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, Taipei, Taiwan. Program in Molecular Medicine, School of Life Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Man-Hsin
authors.initials: MH
authors.lastname: Hung
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Li-Ju
authors.initials: LJ
authors.lastname: Chen
authors.affiliation: Graduate Institute of Medical Genomics and Proteomics, National Taiwan University College of Medicine, Taipei, Taiwan.
authors.forename: Pei-Lung
authors.initials: PL
authors.lastname: Chen
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Jung-Chen
authors.initials: JC
authors.lastname: Su
authors.affiliation: Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.
authors.forename: Ping-Yi
authors.initials: PY
authors.lastname: Lin
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan.
authors.forename: Hui-Chuan
authors.initials: HC
authors.lastname: Yu
authors.affiliation: Department of Medical Research, National Taiwan University Hospital, Taipei, Taiwan. National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, Taipei, Taiwan. kfchen1970@ntu.edu.tw.
authors.forename: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000368:Aged; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D006528:Carcinoma, Hepatocellular / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D015897:Comorbidity; D004195:Disease Models, Animal; D018450:Disease Progression; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D010671:Phenylurea Compounds / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000737:chemistry / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology*; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays; D018909:src Homology Domains
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D050796:STAT3 Transcription Factor; C559147:regorafenib; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6