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 |
| 卷 | 35 |
| 發行號 | 45 |
| DOIs | |
| 出版狀態 | Published - 2016 十一月 10 |
指紋
All Science Journal Classification (ASJC) codes
- Molecular Biology
- Genetics
- Cancer Research
引用此文
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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, Shao-Chieh; Lin, Shih-Chieh; Lin, Po-Wen; Lee, Jenq-Chang; Chang, Y. J.; Sun, Hsiao-Fang; Tsai, Shaw-Jenq.
於: Oncogene, 卷 35, 編號 45, 10.11.2016, p. 5872-5881.研究成果: Article
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 -