title: Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma.
abstract: Protein tyrosine phosphatase 1B (PTP1B) is known to promote the pathogenesis of diabetes and obesity by negatively regulating insulin and leptin pathways, but its role associated with colon carcinogenesis is still under debate. In this study, we demonstrated the oncogenic role of PTP1B in promoting colon carcinogenesis and predicting worse clinical outcomes in CRC patients. By co-immunoprecipitation, we showed that PITX1 was a novel substrate of PTP1B. Through direct dephosphorylation at Y160, Y175 and Y179, PTP1B destabilized PITX1, which resulted in downregulation of the PITX1/p120RasGAP axis. Interestingly, we found that regorafenib, the approved target agent for advanced CRC patients, exerted a novel property against PTP1B. By inhibiting PTP1B activity, regorafenib treatment augmented the stability of PITX1 protein and upregulated the expression of p120RasGAP in CRC. Importantly, we found that this PTP1B-dependant PITX1/p120RasGAP axis determines the in vitro anti-CRC effects of regorafenib. The above-mentioned effects of regorafenib were confirmed by the HT-29 xenograft tumor model. In conclusion, we demonstrated a novel oncogenic mechanism of PTP1B on affecting PITX1/p120RasGAP in CRC. Regorafenib inhibited CRC survival through reserving PTP1B-dependant PITX1/p120RasGAP downregulation. PTP1B may be a potential biomarker predicting regorafenib effectiveness, and a potential solution for CRC.
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Teng
authors.affiliation: Division of Medical Oncology, Department of Oncology, Taipei Veterans General Hospital, Taipei, Taiwan.|School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Program in Molecular Medicine, School of Life Science, 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: 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: Mao-Ju
authors.initials: MJ
authors.lastname: Chang
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: Feng-Shu
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: Ming-Hsien
authors.initials: MH
authors.lastname: Tsai
authors.affiliation: Industrial Technology Research Institute, Hsin-Chu, Taiwan.
authors.forename: Jui-Wen
authors.initials: JW
authors.lastname: Huang
authors.affiliation: Industrial Technology Research Institute, Hsin-Chu, Taiwan.
authors.forename: Chih-Lung
authors.initials: CL
authors.lastname: Lin
authors.affiliation: Industrial Technology Research Institute, Hsin-Chu, Taiwan.
authors.forename: Hsiang-Wen
authors.initials: HW
authors.lastname: Tseng
authors.affiliation: Industrial Technology Research Institute, Hsin-Chu, Taiwan.
authors.forename: Zong-Keng
authors.initials: ZK
authors.lastname: Kuo
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Colon &Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Jeng-Kai
authors.initials: JK
authors.lastname: Jiang
authors.affiliation: School of Medicine, National Yang-Ming University, Taipei, Taiwan.|Division of Colon &Rectal Surgery, Department of Surgery, Taipei Veterans General Hospital, Taipei, Taiwan.
authors.forename: Shung-Haur
authors.initials: SH
authors.lastname: Yang
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 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: Kuen-Feng
authors.initials: KF
authors.lastname: Chen
mesh_terms: D000368:Aged; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019073:HT29 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008875:Middle Aged; D051761:Paired Box Transcription Factors / Q000235:genetics*; D010671:Phenylurea Compounds / Q000008:administration & dosage; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1 / Q000235:genetics*; D011725:Pyridines / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays; D020729:p120 GTPase Activating Protein / Q000235:genetics*
chemical_list: D051761:Paired Box Transcription Factors; D010671:Phenylurea Compounds; D011725:Pyridines; C101485:homeobox protein PITX1; D020729:p120 GTPase Activating Protein; C559147:regorafenib; C516607:PTPN1 protein, human; D054562:Protein Tyrosine Phosphatase, Non-Receptor Type 1