Cadherin 6 Is a New RUNX2 Target in TGF-β Signalling Pathway

Abstract

Modifications in adhesion molecules profile may change the way tumor cells interact with the surrounding microenvironment. The Cadherin family is a large group of transmembrane proteins that dictate the specificity of the cellular interactions. The Cadherin switch that takes place during epithelial-mesenchymal transition (EMT) contributes to loosening the rigid organization of epithelial tissues and to enhancing motility and invasiveness of tumor cells. Recently, we found Cadherin-6 (CDH6, also known as K-CAD) highly expressed in thyroid tumor cells that display mesenchymal features and aggressive phenotype, following the overexpression of the transcriptional regulator Id1. In this work, we explored the possibility that CDH6 is part of the EMT program in thyroid tumors. We demonstrate that CDH6 is a new transforming growth factor-β (TGF-β) target and that its expression is modulated similarly to other EMT mesenchymal markers, both in vitro and in thyroid tumor patients. We show for the first time that CDH6 is expressed in human thyroid carcinomas and that its expression is enhanced at the invasive front of the tumor. Finally, we show that CDH6 is under the control of the transcription factor RUNX2, which we previously described as a crucial mediator of the Id1 pro-invasive function in thyroid tumor cells. Overall, these observations provide novel information on the mechanism of the EMT program in tumor progression and indicate CDH6 as a potential regulator of invasiveness in thyroid tumors.

Hydrogen Peroxide Enhances TGFβ-mediated Epithelial-to-Mesenchymal Transition in Human Mammary Epithelial MCF-10A Cells

“…MEK/ERK, JNK, and p38 are critical components of noncanonical, SMAD-independent TGFβ signaling (13). Of these, ERK1/2 is also known to regulate SNAIL1, SNAIL2 and ZEB1 expression (21,22). MEK/ERK phosphorylation was enhanced by both H 2 O 2 and irradiation in TGFβ-treated cells (Figure 4), as previously reported (15).…”

Inflammatory mediators, tumor necrosis factor-α and interferon-γ, induce EMT in human PTC cell lines

“…N-cadherin mRNA and protein levels were upregulated following incubation with TNF-α, but no changes were observed in the level of N-cadherin expression following incubation with IFN-γ. Loss of E-cadherin and gain of N-cadherin is defined as 'cadherin switch' and indicates EMT in numerous solid tumors (10,11,13). However, increased expression of N-cadherin is not observed in all cells undergoing EMT.…”

“…TNF-α and IFN-γ are pleiotropic cytokines expressed in various types of tumor cells and cells in the tumor microenvironment, exerting a variety of pro-tumoral activities in solid tumors (10,11). Recent research into the inflammatory microenvironment of malignant PTC tissues has supported the hypothesis that a close association exists between inflammation and tumor metastasis progression (12,13). Despite attempts in the last few decades to elucidate the inflammatory cytokines underlying invasion and metastasis in PTC patients, the understanding about the role of TNF-α and IFN-γ in PTC is limited.…”

Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy

“…19,20 Recently, we found CDH6 as strongly expressed in a model of highly aggressive thyroid cancer, and we showed that CDH6 expression is induced by TGFβ during EMT in thyroid cancer cells. 21,22 These observations suggest that CDH6 is part of a program that supports aggressiveness of thyroid tumors. In this work, we investigated the biological role of CDH6 in thyroid cancer cells and the molecular mechanisms through which this protein partake to thyroid cancer progression.…”