title: Protein tyrosine phosphatase 1B dephosphorylates PITX1 and regulates p120RasGAP in hepatocellular carcinoma.
abstract: The effective therapeutic targets for hepatocellular carcinoma remain limited. Pituitary homeobox 1 (PITX1) functions as a tumor suppressor in hepatocarcinogenesis by regulating the expression level of Ras guanosine triphosphatase-activating protein. Here, we report that protein tyrosine phosphatases 1B (PTP1B) directly dephosphorylated PITX1 at Y160, Y175, and Y179 to further weaken the protein stability of PITX. The PTP1B-dependent decline of PITX1 reduced its transcriptional activity for p120RasGAP (RASA1), a Ras guanosine triphosphatase-activating protein. Both silencing of PTP1B and PTP1B inhibitor up-regulated the PITX1-p120RasGAP axis through hyperphosphorylation of PITX1. Sorafenib, the first and only targeted drug approved for hepatocellular carcinoma, directly decreased PTP1B activity and promoted the expression of PITX1 and p120RasGAP by PITX1 hyperphosphorylation. Molecular docking also supported the potential interaction between PTP1B and sorafenib. PTP1B overexpression impaired the sensitivity of sorafenib in vitro and in vivo, implying that PTP1B has a significant effect on sorafenib-induced apoptosis. In sorafenib-treated tumor samples, we further found inhibition of PTP1B activity and up-regulation of the PITX1-p120RasGAP axis, suggesting that PTP1B inhibitor may be effective for the treatment of hepatocellular carcinoma. By immunohistochemical staining of hepatic tumor tissue from 155 patients, the expression of PTP1B was significantly in tumor parts higher than nontumor parts (P = 0.02). Furthermore, high expression of PTP1B was significantly associated with poor tumor differentiation (P = 0.031).
  
  
  CONCLUSIONS
  PTP1B dephosphorylates PITX1 to weaken its protein stability and the transcriptional activity for p120RasGAP gene expression and acts as a determinant of the sorafenib-mediated drug effect; targeting the PITX1-p120RasGAP axis with a PTP1B inhibitor may provide a new therapy for patients with hepatocellular carcinoma.
authors: 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: Wei-Tien
authors: WT
authors: Tai
authors: Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan.|School of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan.
authors: Yao-Li
authors: YL
authors: Chen
authors: Department of Pathology, Show Chwan Memorial Hospital, Changhua City, Taiwan.|School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan.
authors: Pei-Yi
authors: PY
authors: Chu
authors: 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: Li-Ju
authors: LJ
authors: Chen
authors: 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: Man-Hsin
authors: MH
authors: Hung
authors: Institute of Biopharmaceutical Sciences, National Yang-Ming University, Taipei, Taiwan.
authors: Chung-Wai
authors: CW
authors: Shiau
authors: Industrial Technology Research Institute, Hsin-Chu, Taiwan.
authors: Jui-Wen
authors: JW
authors: Huang
authors: 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: Ming-Hsien
authors: MH
authors: Tsai
authors: 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: Kuen-Feng
authors: KF
authors: Chen
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008958:Models, Molecular; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D051761:Paired Box Transcription Factors / Q000378:metabolism*; D010671:Phenylurea Compounds / Q000494:pharmacology; D010766:Phosphorylation; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000502:physiology*; D000077157:Sorafenib; D020729:p120 GTPase Activating Protein / Q000235:genetics*
chemical_list: D051761:Paired Box Transcription Factors; D010671:Phenylurea Compounds; C101485:homeobox protein PITX1; D020729:p120 GTPase Activating Protein; D009536:Niacinamide; D000077157:Sorafenib; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1