Download Targeting TYRO3 inhibits epithelial*mesenchymal transition and

Targeting TYRO3 inhibits epithelial–mesenchymal transition and increases drug
sensitivity in colon cancer
論文出處(期刊)：Oncogene 35, 38 (2016)
演講者(中英文)：蔡悠恬(You-Tien Tsai)
指導老師(中英文)：林雅雯 (Ya-Wen Lin), PhD
演講日期：2016.11.04
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.
1. 選此論文的原因：
由於本實驗室主要研究的主題與癌症相關，讀此篇文章可以藉此增加我對大腸直腸癌(CRC)
與 RTK(Receptor Tyrosine Kinase)相關研究的了解。
2. 學習重點：
(1) 了解 TAM family 目前已知在細胞中所扮演的角色及與癌症的關係。
(2) TAM family 中的 TYRO3，在 CRC 中扮演 oncogene 的角色。
(3) 了解 TYRO3 與 EMT(epithelial–mesenchymal transition) process 發生有正相關性
(4) 本篇研究中，發現 TYRO3 會透過 SNAI1 促使 EMT process 發生，且作者利用自製的
anti-TYRO3 human antibodies (hIgG)使得腫瘤生成能力下降並支持 TYRO3 是一個具有潛力
的 CRC 治療標的。
3. 討論的問題：
(1)TYRO3 是經由甚麼機制來影響癌症的轉移？
(2)TAM family 是屬於哪種功能性蛋白質？
(3)為什麼此篇文章中提到 TYRO3 可以在 CRC 中是一個有潛力的治療標的？