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BACKGROUND: During 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. METHODS: The 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. RESULTS: Induction 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. CONCLUSION: Taken 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.

Original publication

DOI

10.1186/s12885-017-3537-5

Type

Journal article

Journal

BMC Cancer

Publication Date

15/08/2017

Volume

17

Keywords

AGR2, E-cadherin, EMT, Metastasis, TGF-β, Vimentin, Cadherins, Cell Adhesion, Cell Line, Tumor, Cell Movement, Epithelial-Mesenchymal Transition, Gene Expression Regulation, Neoplastic, Gene Knockdown Techniques, Humans, Mucoproteins, Oncogene Proteins, Proteins, Signal Transduction, Smad Proteins, Transforming Growth Factor beta, Vimentin