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, Shao-Chieh Lin, Shih-Chieh Lin, Po-Wen Lin, Jenq-Chang Lee, Y. J. Chang, Hsiao-Fang Sun, Shaw-Jenq Tsai

研究成果: Article

16 引文 (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English
頁(從 - 到)5872-5881
頁數10
期刊Oncogene
35
發行號45
DOIs
出版狀態Published - 2016 十一月 10

指紋

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

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Cancer Research

引用此文

@article{bca5f85ff8dd4468b45326155cb2ea10,
title = "Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer",
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.",
author = "Chien, {C. W.} and Hou, {P. C.} and Wu, {H. C.} and Chang, {Y. L.} and Shao-Chieh Lin and Shih-Chieh Lin and Po-Wen Lin and Jenq-Chang Lee and Chang, {Y. J.} and Hsiao-Fang Sun and Shaw-Jenq Tsai",
year = "2016",
month = "11",
day = "10",
doi = "10.1038/onc.2016.120",
language = "English",
volume = "35",
pages = "5872--5881",
journal = "Oncogene",
issn = "0950-9232",
publisher = "Nature Publishing Group",
number = "45",

}

TY - JOUR

T1 - Targeting TYRO3 inhibits epithelial-mesenchymal transition and increases drug sensitivity in colon cancer

AU - Chien, C. W.

AU - Hou, P. C.

AU - Wu, H. C.

AU - Chang, Y. L.

AU - Lin, Shao-Chieh

AU - Lin, Shih-Chieh

AU - Lin, Po-Wen

AU - Lee, Jenq-Chang

AU - Chang, Y. J.

AU - Sun, Hsiao-Fang

AU - Tsai, Shaw-Jenq

PY - 2016/11/10

Y1 - 2016/11/10

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84964790940&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84964790940&partnerID=8YFLogxK

U2 - 10.1038/onc.2016.120

DO - 10.1038/onc.2016.120

M3 - Article

C2 - 27132510

AN - SCOPUS:84964790940

VL - 35

SP - 5872

EP - 5881

JO - Oncogene

JF - Oncogene

SN - 0950-9232

IS - 45

ER -