Thyroid Transcription Factor-1 Inhibits Transforming Growth Factor-–Mediated Epithelial-to-Mesenchymal Transition in Lung Adenocarcinoma Cells

¹Departments of Molecular Pathology and ²Respiratory Medicine, Graduate School of Medicine, University of Tokyo, Tokyo, Japan

^* To whom correspondence should be addressed. E-mail: miyazono-ind{at}umin.ac.jp.

	Abstract

Thyroid transcription factor-1 (TTF-1) is expressed in lung cancer, but its functional roles remain unexplored. TTF-1 gene amplification has been discovered in a part of lung adenocarcinomas, and its action as a lineage-specific oncogene is highlighted. Epithelial-to-mesenchymal transition (EMT) is a crucial event for cancer cells to acquire invasive and metastatic phenotypes and can be elicited by transforming growth factor- (TGF-). Mesenchymal-to-epithelial transition (MET) is the inverse process of EMT; however, signals that induce MET are largely unknown. Here, we report a novel functional aspect of TTF-1 that inhibits TGF-–mediated EMT and restores epithelial phenotype in lung adenocarcinoma cells. This effect was accompanied by down-regulation of TGF- target genes, including presumed regulators of EMT, such as Snail and Slug. Moreover, silencing of TTF-1 enhanced TGF-–mediated EMT. Thus, TTF-1 can exert a tumor-suppressive effect with abrogation of cellular response to TGF- and attenuated invasive capacity. We further revealed that TTF-1 down-regulates TGF-2 production in A549 cells and that TGF- conversely decreases endogenous TTF-1 expression, suggesting that enhancement of autocrine TGF- signaling accelerates the decrease of TTF-1 expression and vice versa. These findings delineate potential links between TTF-1 and TGF- signaling in lung cancer progression through regulation of EMT and MET and suggest that modulation of TTF-1 expression can be a novel therapeutic strategy for treatment of lung adenocarcinoma. [Cancer Res 2009;69(7):OF1–9]

Key Words: TTF-1, Nkx2.1, EMT, MET, TGF-