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

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-B (TGF-B). 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-B-mediated EMT and restores epithelial phenotype in lung adenocarcinoma cells. This effect was accompanied by down-regulation of TGF-B target genes, including presumed regulators of EMT, such as Snail and Slug. Moreover, silencing of TTF-1 enhanced TGF-B-mediated EMT. Thus, TTF-1 can exert a tumor-suppressive effect with abrogation of cellular response to TGF-B and attenuated invasive capacity. We further revealed that TTF-1 downregulates TGF-B2 production in A549 cells and that TGF-B conversely decreases endogenous TTF-1 expression, suggesting that enhancement of autocrine TGF-B signaling accelerates the decrease of TTF-1 expression and vice versa. These findings delineate potential links between TTF-1 and TGF-B 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.

Induction of EMT-like phenotypes by an active metabolite of leflunomide and its contribution to pulmonary fibrosis

“…Thus, we tested the contribution of SIP1 to A771726-induced EMT-like phenotypes using its siRNA (unfortunately, we could not obtain siRNA that efficiently suppresses the It has also been reported that TGF-b 1 upregulates the expression of EMT-related transcription factors, including SIP1. 23,24 However, as shown in Supplementary Figure S2a Next, we tested the contribution of the Notch-signaling pathway to A771726-induced EMT-like phenotypes. This pathway, which is triggered by the binding between Notch receptors (Notch-1-4) and ligands (such as Jagged-1, 2 and Delta-like 1 (Dll-1)), is mediated by two proteolytic cleavage events involving the Notch receptor.…”

MiR-365 regulates lung cancer and developmental gene thyroid transcription factor 1

“…We believe that there is a significant crosstalk between the transcriptional program and miRNA network in the lung (diseased or normal), and miR-365 is merely "a tip of an iceberg." In the intriguing signaling loop reported by Saito et al, TGFβ induced TTF-1 downregulation, thus blunting the anti-EMT activity associated with TTF-1, 27 but the molecules mediating this activity were unidentified. In this study, we present evidence that miR-365 mediates TTF-1 repression by TGFβ.…”

“…Saito et al recently reported that TTF-1 inhibits TGFβ-mediated EMT in lung cancer cells, 27 suggesting that TTF-1 is an anti-EMT factor. In their study, TGFβ treatment led to downregulation of TTF-1, blunting the anti-EMT phenotype conferred by the TTF-1 protein.…”

“…An observation made by Saito et al was that TTF-1 would blunt TGFβ signaling by suppressing TGFβ2 expression. 27 We were thus curious if miR-365 would induce TGFβ expression as a means to further counter the anti-TGFβ effect of TTF-1. The RNA expression of TGFβ1~3 was determined using RT-QPCR in the H441-based stable transfectant cells.…”

“…Saito et al reported an unexpected activity of TTF-1: inhibition of TGFβ-induced EMT by TTF-1. 27 They further demonstrated that enhancement of autocrine TGFβ signaling would decrease TTF-1 expression, thus blunting the anti-EMT effect derived from TTF-1. 27 However, the molecular mechanism accounting for how TGFβ modulates TTF-1 expression was not elucidated in the study.…”