Increased PTP1B expression and phosphatase activity in colorectal cancer results in a more invasive phenotype and worse patient outcome

Hoekstra, Elmer; Das, Asha; Swets, Marloes; Cao, Wanlu; Woude, C. Janneke van der; Bruno, Marco J.; Peppelenbosch, Maikel P.; Kuppen, Peter J. K.; Hagen, Timo L.M. ten; Fuhler, Gwenny M.

doi:10.18632/oncotarget.7829

Cited by 59 publications

(46 citation statements)

References 48 publications

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“…Recently, Gunawardana et al reported [16] a high frequency of somatic coding-sequence mutations in PTPN1, the gene for encoding PTP1B, in primary mediastinal B cell lymphoma (PMBCL) and Hodgkin lymphoma, and concluded that these PTPN1 mutations are drivers of lymphomagenesis. Notably, it was shown recently that using cbioportal, Hoekstra et al analyzed the TCGA colorectal cancer dataset, revealing an alteration of PTPN1 in 45% (88 out of 195) of the CRC cases with frequent amplifications and only few mutation[24]. However, in our study, nearly 50% of colon tumors have a mutation in PTPN1.…”

Section: Discussioncontrasting

confidence: 49%

Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors

et al. 2016

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Expression of wild-type protein tyrosine phosphatase (PTP) 1B may act either as a tumor suppressor by dysregulation of protein tyrosine kinases or a tumor promoter through Src dephosphorylation at Y527 in human breast cancer cells. To explore whether mutated PTP1B is involved in human carcinogenesis, we have sequenced PTP1B cDNAs from human tumors and found splice mutations in ~20% of colon and thyroid tumors. The PTP1BΔE6 mutant expressed in these two tumor types and another PTP1BΔE5 mutant expressed in colon tumor were studied in more detail. Although PTP1BΔE6 revealed no phosphatase activity compared with wild-type PTP1B and the PTP1BΔE5 mutant, its expression induced oncogenic transformation of rat fibroblasts without Src activation, indicating that it involved signaling pathways independent of Src. The transformed cells were tumourigenic in nude mice, suggesting that the PTP1BΔE6 affected other molecule(s) in the human tumors. These observations may provide a novel therapeutic target for colon and thyroid cancer.

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Section: Discussioncontrasting

confidence: 49%

Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors

et al. 2016

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“…1). Our results echoed the findings of the other two groups1819. Furthermore, we showed a significant positive correlation between PTP1B and p-Erk, one important indicator for activation of Ras signaling (Supplement Figure 5), supporting the importance of PTP1B in regulating Ras signaling.…”

Section: Discussionsupporting

confidence: 89%

“…For CRC, Zhu et al . described a positive role for PTP1B in the promotion of colon carcinogenesis through Src Activation17, and overexpression of PTP1B was found to be an important prognostic factor in CRC patients1819. Intriguingly, Tremblay and colleagues suggested that PTP1B has a positive regulatory role in Ras activity by finding that upregulation of p120 Ras GTPase-activating protein (p120RasGAP, RASA1) and p62Dok phosphorylation were presented in PTP1B-deficient fibroblasts8.…”

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confidence: 99%

Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma

Teng

Hung

Chen

et al. 2016

Sci Rep

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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.

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“…32 We show here that the cell death induced by inhibition/knockdown of PTP1B and CPT-induced apoptosis demonstrates morphology representative of anoikis and classical apoptosis, respectively. We also provide evidence that PTP1B can activate Src, a well-known oncogene, which is known to have a role in anoikis.…”

Section: Discussionmentioning

confidence: 67%

Inhibition of PTP1B disrupts cell–cell adhesion and induces anoikis in breast epithelial cells

et al. 2017

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Protein tyrosine phosphatase 1B (PTP1B) is a well-known inhibitor of insulin signaling pathways and inhibitors against PTP1B are being developed as promising drug candidates for treatment of obesity. PTP1B has also been linked to breast cancer both as a tumor suppressor and as an oncogene. Furthermore, PTP1B has been shown to be a regulator of cell adhesion and migration in normal and cancer cells. In this study, we analyzed the PTP1B expression in normal breast tissue, primary breast cells and the breast epithelial cell line D492. In normal breast tissue and primary breast cells, PTP1B is widely expressed in both epithelial and stromal cells, with highest expression in myoepithelial cells and fibroblasts. PTP1B is widely expressed in branching structures generated by D492 when cultured in 3D reconstituted basement membrane (3D rBM). Inhibition of PTP1B in D492 and another mammary epithelial cell line HMLE resulted in reduced cell proliferation and induction of anoikis. These changes were seen when cells were cultured both in monolayer and in 3D rBM. PTP1B inhibition affected cell attachment, expression of cell adhesion proteins and actin polymerization. Moreover, epithelial to mesenchymal transition (EMT) sensitized cells to PTP1B inhibition. A mesenchymal sublines of D492 and HMLE (D492M and HMLEmes) were more sensitive to PTP1B inhibition than D492 and HMLE. Reversion of D492M to an epithelial state using miR-200c-141 restored resistance to detachment induced by PTP1B inhibition. In conclusion, we have shown that PTP1B is widely expressed in the human breast gland with highest expression in myoepithelial cells and fibroblasts. Inhibition of PTP1B in D492 and HMLE affects cell–cell adhesion and induces anoikis-like effects. Finally, cells with an EMT phenotype are more sensitive to PTP1B inhibitors making PTP1B a potential candidate for further studies as a target for drug development in cancer involving the EMT phenotype.

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Increased PTP1B expression and phosphatase activity in colorectal cancer results in a more invasive phenotype and worse patient outcome

Cited by 59 publications

References 48 publications

Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors

Cell Transformation by PTP1B Truncated Mutants Found in Human Colon and Thyroid Tumors

Protein tyrosine phosphatase 1B targets PITX1/p120RasGAP thus showing therapeutic potential in colorectal carcinoma

Inhibition of PTP1B disrupts cell–cell adhesion and induces anoikis in breast epithelial cells

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