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

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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.

Original languageEnglish
Pages (from-to)5872-5881
Number of pages10
JournalOncogene
Volume35
Issue number45
DOIs
Publication statusPublished - Nov 10 2016

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Epithelial-Mesenchymal Transition
Colonic Neoplasms
Pharmaceutical Preparations
Oncogenes
Antibodies
Polyps
Cell Movement
Meta-Analysis
Cause of Death
Anti-Idiotypic Antibodies
Neoplasms
Survival Rate
Staining and Labeling
Mutation
Growth

Cite this

Chien, C-W., Hou, P-C., Wu, H-C., Chang, Y-L., Lin, S-C., Lin, S-C., ... 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

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

In: Oncogene, Vol. 35, No. 45, 10.11.2016, p. 5872-5881.

Research output: Contribution to journalArticle

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, HS & Tsai, S-J 2016, 'Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer', Oncogene, vol. 35, no. 45, pp. 5872-5881. https://doi.org/10.1038/onc.2016.120
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. / Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer. In: Oncogene. 2016 ; Vol. 35, No. 45. pp. 5872-5881.
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