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.
Highlights
Colorectal carcinoma (CRC) is the third most common cancer in the world, with more than 1.3 million new cases diagnosed annually[1]
Given the crucial role of Ras signaling in insulin receptor signaling[9,20] and colon carcinogenesis[3,21], it is of great interest to explore the cross talk between Protein tyrosine phosphatase 1B (PTP1B) and Ras signaling in CRC
We further identified that regorafenib, a multi-kinase inhibitor that has been approved for chemo-refractory metastatic CRC patients[23], modulates PTP1B/PITX-1/p120RasGAP signaling in CRC
Summary
Colorectal carcinoma (CRC) is the third most common cancer in the world, with more than 1.3 million new cases diagnosed annually[1]. Factor receptor[13,14,15]; a growing body of evidence supports the notion that PTP1B is actively involved in promoting carcinogenesis by interacting with several oncogenic substrates, including HER2/Neu, ERK1/2, p62Dok and Src[8,16,17]. For CRC, Zhu et al described a positive role for PTP1B in the promotion of colon carcinogenesis through Src Activation[17], and overexpression of PTP1B was found to be an important prognostic factor in CRC patients[18,19]. We show that the expression of PTP1B in clinical CRC tumors is negatively correlated with p120RasGAP, but positive correlated with p-Erk expression, one indicator for activation of Ras signaling. We further identified that regorafenib, a multi-kinase inhibitor that has been approved for chemo-refractory metastatic CRC patients[23], modulates PTP1B/PITX-1/p120RasGAP signaling in CRC
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
