Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition
Abstract 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...
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| Format: | Article |
| Language: | English |
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BMC
2017-08-01
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| Series: | BMC Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12885-017-3537-5 |
| _version_ | 1819146067123372032 |
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| author | Lucia Sommerova Eva Ondrouskova Borivoj Vojtesek Roman Hrstka |
| author_facet | Lucia Sommerova Eva Ondrouskova Borivoj Vojtesek Roman Hrstka |
| author_sort | Lucia Sommerova |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-22T13:08:01Z |
| format | Article |
| id | doaj.art-f2e9f83329c04413a439dee225eceb1e |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-22T13:08:01Z |
| publishDate | 2017-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Cancer |
| spelling | doaj.art-f2e9f83329c04413a439dee225eceb1e2022-12-21T18:24:49ZengBMCBMC Cancer1471-24072017-08-0117111110.1186/s12885-017-3537-5Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transitionLucia Sommerova0Eva Ondrouskova1Borivoj Vojtesek2Roman Hrstka3RECAMO, Masaryk Memorial Cancer InstituteRECAMO, Masaryk Memorial Cancer InstituteRECAMO, Masaryk Memorial Cancer InstituteRECAMO, Masaryk Memorial Cancer InstituteAbstract 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.http://link.springer.com/article/10.1186/s12885-017-3537-5AGR2EMTTGF-βE-cadherinVimentinMetastasis |
| spellingShingle | Lucia Sommerova Eva Ondrouskova Borivoj Vojtesek Roman Hrstka Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition BMC Cancer AGR2 EMT TGF-β E-cadherin Vimentin Metastasis |
| title | Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition |
| title_full | Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition |
| title_fullStr | Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition |
| title_full_unstemmed | Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition |
| title_short | Suppression of AGR2 in a TGF-β-induced Smad regulatory pathway mediates epithelial-mesenchymal transition |
| title_sort | suppression of agr2 in a tgf β induced smad regulatory pathway mediates epithelial mesenchymal transition |
| topic | AGR2 EMT TGF-β E-cadherin Vimentin Metastasis |
| url | http://link.springer.com/article/10.1186/s12885-017-3537-5 |
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