title: SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma.
abstract: Epithelial-to-mesenchymal transition (EMT) is well known to involve in tumor invasion and metastasis. Src homology region 2 domain-containing phosphatase 1 (SHP-1) functions as a potent tumor suppressor and also acts as a negative regulator of p-STAT3(Tyr705) oncogenic signaling. However, little is known about the molecular mechanism(s) through which SHP-1 regulates EMT during hepatocellular carcinoma (HCC) progression. Here we first reported that endogenous SHP-1 protein levels were significantly downregulated in cells with mesenchymal characteristics and negatively correlated with p-STAT3(Tyr705) and vimentin but positively correlated with E-cadherin. SHP-1 overexpression abolished transforming growth factor-β1 (TGF-β1)-induced p-STAT3(Tyr705) and EMT, as well inhibited migration and invasion but further rescued by signal transducer and activator of transcription factor 3 (STAT3) overexpression. Depletion of SHP-1 could induce a more increase in TGF-β1-induced p-STAT3(Tyr-705) and EMT characteristics, further supporting the mechanism that suppression of TGF-β1-induced EMT is dependent on SHP-1-mediated STAT3 inactivation. Constitutively overexpressed SHP-1 tyrosine phosphatase activity by D61A-mutated SHP-1 markedly reduced TGF-β1-induced p-STAT3(Tyr705) and EMT features but was not altered by C453S catalytic-dead mutant SHP-1. Consequently, SHP-1 acted as a powerful suppressor in preventing EMT by exerting its tyrosine phosphatase activity that directly downregulated p-STAT3(Tyr705). Most notably, we discovered a novel SHP-1 agonist SC-43 better than sorafenib to exert more potent anti-EMT effects in vitro as well as anti-metastatic growth in vivo. In conclusion, SHP-1 is a potent suppressor of HCC EMT and metastasis, thus highlighting that SC-43-SHP-1 axis may serve as a potential therapeutic target that antagonized p-STAT3(Tyr705) and thereby prevented HCC EMT and metastasis.
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: L-C
authors.initials: LC
authors.lastname: Fan
authors.affiliation: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors.forename: C-W
authors.initials: CW
authors.lastname: Shiau
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: W-T
authors.initials: WT
authors.lastname: Tai
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: M-H
authors.initials: MH
authors.lastname: Hung
authors.affiliation: Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan.|School of Medicine, College of Medicine, Fu Jen Catholic University, Xinzhuang Dist., New Taipei City, Taiwan.
authors.forename: P-Y
authors.initials: PY
authors.lastname: Chu
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: F-S
authors.initials: FS
authors.lastname: Hsieh
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: H
authors.initials: H
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: H-C
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.
authors.forename: K-F
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000201:enzymology* / Q000556:secondary; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology* / Q000473:pathology; D008175:Lung Neoplasms / Q000201:enzymology* / Q000556:secondary; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6 / Q000502:physiology*; D050796:STAT3 Transcription Factor / Q000378:metabolism
chemical_list: D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6