Abstract
Colon cancer is the third leading cause of death from cancer worldwide with less than 10% survival rate at the late stage. Although mutations of certain genes have been implicated in familial colon cancer development, the etiology of the majority of colon cancer remains unknown. Herein, we identified TYRO3 as a potential oncogene. Immunohistochemical staining results demonstrated that levels of TYRO3 were markedly elevated in polyps and colon cancer cells and were negatively correlated with prognosis. Overexpression of TYRO3 enhanced cell motility, invasion, anchorage-independent growth and metastatic ability, while knockdown of TYRO3 impaired all these processes. Results from meta-analysis showed that TYRO3 was associated with epithelial–mesenchymal transition (EMT) signatures. Gain-of-function and loss-of-function experiments demonstrated that expression of SNAI1, the master regulator of EMT, was regulated by TYRO3 and played a major role in mediating TYRO3-induced EMT processes. The murine model also demonstrated that Tyro3 and Snai1 were upregulated in the early stage of colon cancer development. To provide a proof-of-concept that TYRO3 is a druggable target in colon cancer therapy, we raised anti-TYRO3 human antibodies and showed that treatment with the human antibody abolished TYRO3-induced EMT process. More importantly, administration of this anti-TYRO3 antibody increased drug sensitivity in primary cultured colon cancer cells and xenografted mouse tumors. These findings demonstrate that TYRO3 is a novel oncogene and a druggable target in colon cancer.
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Acknowledgements
We thank Miss Yi-Hsuan Yeh and Miss Yi-Chen Tang for technical assistance with IHC and animal study. This work was supported by grants from National Science Council of Taiwan (NSC 101-2321-B-006-020 and NSC 102-2321-B-006-011) and by Top University Grant of National Cheng Kung University (grant # D103-35A17).
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CWC and PCH performed most experiments; HCW and YLC produced and tested human monoclonal antibody; SCL, BWL, JCL and YJC participated and conducted experiments using clinical samples; HSS and SJT conceived the project; and CWC, HSS and SJT wrote the manuscript. All authors read and approved the final version of manuscript.
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Chien, CW., Hou, PC., Wu, HC. et al. Targeting TYRO3 inhibits epithelial–mesenchymal transition and increases drug sensitivity in colon cancer. Oncogene 35, 5872–5881 (2016). https://doi.org/10.1038/onc.2016.120
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DOI: https://doi.org/10.1038/onc.2016.120
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