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PTPRB promotes metastasis of colorectal carcinoma via inducing epithelial-mesenchymal transition.

ABSTRACT: Dysregulation of protein tyrosine phosphatase, receptor type B (PTPRB) correlates with the development of a variety of tumors. Here we show that PTPRB promotes metastasis of colorectal cancer (CRC) cells via inducing epithelial-mesenchymal transition (EMT). We find that PTPRB is expressed at significantly higher levels in CRC tissues compared to adjacent nontumor tissues and in CRC cell lines with high invasion. PTPRB knockdown decreased the number of invasive CRC cells in an in vitro wound healing model, and also reduced tumor metastasis in vivo. Conversely, PTPRB overexpression promoted CRC cell invasion in vitro and metastasis in vivo. PTPRB overexpression decreased vimentin expression and promoted E-cadherin expression, consistent with promotion of EMT, while PTPRB knockdown had the opposite effect. Hypoxic conditions induced EMT and promoted invasion in CRC cells, but these effects were eliminated by PTPRB knockdown. EMT blockade via TWIST1 knockdown inhibited the migration and invasiveness of CRC cells, and even increased PTPRB expression could not reverse this effect. Altogether, these data support the conclusion that PTPRB promotes invasion and metastasis of CRC cells via inducing EMT, and that PTPRB would be a novel therapeutic target for the treatment of CRC.

SUBMITTER: Weng X

PROVIDER: S-EPMC6491493 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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PTPRB promotes metastasis of colorectal carcinoma via inducing epithelial-mesenchymal transition.

Weng Xingyue X Chen Wei W Hu Wangxiong W Xu Kailun K Qi Lina L Chen Jiani J Lu Demin D Shao Yinkuan Y Zheng Xi X Ye Chenyang C Zheng Shu S

Cell death & disease 20190430 5

Dysregulation of protein tyrosine phosphatase, receptor type B (PTPRB) correlates with the development of a variety of tumors. Here we show that PTPRB promotes metastasis of colorectal cancer (CRC) cells via inducing epithelial-mesenchymal transition (EMT). We find that PTPRB is expressed at significantly higher levels in CRC tissues compared to adjacent nontumor tissues and in CRC cell lines with high invasion. PTPRB knockdown decreased the number of invasive CRC cells in an in vitro wound heal ...[more]

PMID: 31040266

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Project description:BackgroundEvading immune surveillance is necessary for tumor metastasis. Thus, there is an urgent need to better understand the interaction between metastasis and mechanisms of tumor immune evasion. In this study, we aimed to clarify a novel mechanism that link tumor metastasis and immunosuppression in the development of esophageal squamous cell carcinoma (ESCC).MethodsThe expression of melanoma-associated antigen C3 (MAGE-C3) was detected using immunohistochemistry. Transwell assays were used to evaluate the migration and invasion ability of esophageal squamous cell carcinoma (ESCC) cells. Metastasis assays in mice were used to evaluate metastatic ability in vivo. Lymphocyte-mediated cytotoxicity assays were performed to visualize the immune suppression function on tumor cells. RNA sequencing was performed to identify differentially expressed genes between MAGE-C3 overexpressing ESCC cells and control cells. Gene ontology (GO) enrichment analyses was performed to identify the most altered pathways influenced by MAGE-C3. The activation of the interferon-γ (IFN-γ) pathway was analyzed using Western blotting, GAS luciferase reporter assays, immunofluorescence, and flow cytometry. The role of MAGE-C3 in the IFN-γ pathway was determined by Western blotting and immunoprecipitation. Furthermore, immunohistochemistry and flow cytometry analysis monitored the changes of infiltrated T cell populations in murine lung metastases.ResultsMAGE-C3 was overexpressed in ESCC tissues. High expression of MAGE-C3 had a significant association with the risk of lymphatic metastasis and poor survival in patients with ESCC. Functional experiments revealed that MAGE-C3 promoted tumor metastasis by activating the epithelial-mesenchymal transition (EMT). MAGE-C3 repressed antitumor immunity and regulated cytokine secretion of T cells, implying an immunosuppressive function. Mechanistically, MAGE-C3 facilitated IFN-γ signaling and upregulated programmed cell death ligand 1 (PD-L1) by binding with IFN-γ receptor 1 (IFNGR1) and strengthening the interaction between IFNGR1 and signal transducer and activator of transcription 1 (STAT1). Interestingly, MAGE-C3 displayed higher tumorigenesis in immune-competent mice than in immune-deficient nude mice, confirming the immunosuppressive role of MAGE-C3. Furthermore, mice bearing MAGE-C3-overexpressing tumors showed worse survival and more lung metastases with decreased CD8+ infiltrated T cells and increased programmed cell death 1 (PD-1)+ CD8+ infiltrated T cells.ConclusionMAGE-C3 enhances tumor metastasis through promoting EMT and protecting tumors from immune surveillance, and could be a potential prognostic marker and therapeutic target.

Dataset Information

PTPRB promotes metastasis of colorectal carcinoma via inducing epithelial-mesenchymal transition.

Publications

PTPRB promotes metastasis of colorectal carcinoma via inducing epithelial-mesenchymal transition.

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