Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition

BMC Cancer

Research Article

Lucia Sommerova¹  Borivoj Vojtesek¹  Roman Hrstka¹  Eva Ondrouskova¹ 

[1] RECAMO, Masaryk Memorial Cancer Institute, Zluty kopec 7, 656 53, Brno, Czech Republic;

关键词: AGR2;    EMT;    TGF-β;    E-cadherin;    Vimentin;    Metastasis;   

DOI  :  10.1186/s12885-017-3537-5

 received in 2017-02-14, accepted in 2017-08-04,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundDuring cancer progression, epithelial cancer cells can be reprogrammed into mesenchymal-like cells with increased migratory potential through the process of epithelial-mesenchymal transition (EMT), representing an essential step of tumor progression towards metastatic state. AGR2 protein was shown to regulate several cancer-associated processes including cellular proliferation, survival and drug resistance.MethodsThe expression of AGR2 was analyzed in cancer cell lines exposed to TGF-β alone or to combined treatment with TGF-β and the Erk1/2 inhibitor PD98059 or the TGF-β receptor specific inhibitor SB431542. The impact of AGR2 silencing by specific siRNAs or CRISPR/Cas9 technology on EMT was investigated by western blot analysis, quantitative PCR, immunofluorescence analysis, real-time invasion assay and adhesion assay.ResultsInduction of EMT was associated with decreased AGR2 along with changes in cellular morphology, actin reorganization, inhibition of E-cadherin and induction of the mesenchymal markers vimentin and N-cadherin in various cancer cell lines. Conversely, induction of AGR2 caused reversion of the mesenchymal phenotype back to the epithelial phenotype and re-acquisition of epithelial markers. Activated Smad and Erk signaling cascades were identified as mutually complementary pathways responsible for TGF-β-mediated inhibition of AGR2.ConclusionTaken together our results highlight a crucial role for AGR2 in maintaining the epithelial phenotype by preventing the activation of key factors involved in the process of EMT.

【 授权许可】

CC BY   
© The Author(s). 2017