TGFβ induces epithelial‐mesenchymal transition of thyroid cancer cells by both the BRAF/MEK/ERK and Src/FAK pathways

Abstract

The epithelial-mesenchymal transition (EMT) is a crucial process in tumour progression, by which epithelial cells acquire a mesenchymal phenotype, increasing its motility and the ability to invade distant sites. Here, we describe the molecular mechanisms by which BRAF, TGFβ and the Src/FAK complex cooperatively regulate EMT induction and cell motility of anaplastic thyroid cancer cells. Analysis of EMT marker levels reveals a positive correlation between TGFβ and Snail expression, with a concomitant downregulation of E-cadherin, accompanied by an increase of cell migration and invasion. Furthermore, we show that BRAF depletion by siRNA or inhibition of its activity by treatment with its inhibitor PLX4720 reverses the TGFβ-mediated effects on Snail, E-cadherin, migration and invasion. Moreover, BRAF induces TGFβ secretion through a MEK/ERK-dependent mechanism. In addition, TGFβ activates the Src/FAK complex, which in turn regulates the expression of Snail and E-cadherin as well as cell migration. The inhibition of Src with the inhibitor SU6656 or abrogation of FAK expression with a specific siRNA reverses the TGFβ-induced effects. Interestingly, we demonstrate that activation of the Src/FAK complex by TGFβ is independent of BRAF signalling, since inhibition of this oncogene does not affect its phosphorylation. Our data strongly suggest that TGFβ induces EMT and aggressiveness of thyroid cancer cells by parallel mechanisms involving both the BRAF/MEK/ERK and Src/FAK pathways independently. Thus, we describe novel functions for Src/FAK in mediating the EMT program and aggressiveness regulated by TGFβ, establishing the inhibition of these proteins as a possible effective approach in preventing tumour progression of BRAF-expressing thyroid tumours. © 2015 Wiley Periodicals, Inc.

Nobiletin inhibits epithelial-mesenchymal transition of human non-small cell lung cancer cells by antagonizing the TGF-β1/Smad3 signaling pathway

“…A novel function for paxillin, Src and FAK has been discovered in mediating EMT and aggressiveness regulated by TGF-β (30)(31)(32). FAK can be activated by a reduction in E-cadherin to facilitate focal adhesion assembly (33).…”

Long non-coding RNA ANRIL promotes the invasion and metastasis of thyroid cancer cells through TGF-β/Smad signaling pathway

“…Importantly, great progress has been achieved in understanding the molecular pathogenesis of TC, as best exemplified by the elucidation of the fundamental role of several major signaling pathways and related molecular derangements [ 20 ]. TGF-β restrains the proliferation of many human cell lines and tissues including thyroid, and a major role of TGF-β/Smad signaling has been suggested in the induction of epithelial-mesenchymal transition (EMT) in TC cells [ 21 , 22 ]. We hypothesized that ANRIL might also play a role in the development of TC through the TGF-β/Smad signaling pathway.…”

ETS1 is coexpressed with ZEB2 and mediates ZEB2‐induced epithelial‐mesenchymal transition in human tumors

“…It is characterized by the repression of E‐cadherin that allows cancer cell to invade and metastasize . A complex network of pathways and transcription factors downregulate cellular adherens and tight junctions to initiate metastatic dissemination of tumors . Of these EMT‐inducing transcription factors, ZEB2 was repeatedly shown to mediate invasion and metastasis of tumors, and to be associated with the progression of the disease and poor prognosis .…”

“…49 A complex network of pathways and transcription factors downregulate cellular adherens and tight junctions to initiate metastatic dissemination of tumors. 10,50,51 Of these EMT-inducing transcription factors, ZEB2…”