Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer

C-W Chien, P-C Hou, H-C Wu, Y-L Chang, S-C Lin, S-C Lin, B-W Lin, J-C Lee, Y-J Chang, H S Sun, S-J Tsai

研究成果: 雜誌貢獻文章

21 引文 斯高帕斯(Scopus)

摘要

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.
原文英語
頁(從 - 到)5872-5881
頁數10
期刊Oncogene
35
發行號45
DOIs
出版狀態已發佈 - 十一月 10 2016

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    Chien, C-W., Hou, P-C., Wu, H-C., Chang, Y-L., Lin, S-C., Lin, S-C., Lin, B-W., Lee, J-C., Chang, Y-J., Sun, H. S., & Tsai, S-J. (2016). Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer. Oncogene, 35(45), 5872-5881. https://doi.org/10.1038/onc.2016.120