Lack of extracellular matrix switches TGF-β induced apoptosis of endometrial cells to epithelial to mesenchymal transition

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Ruiz Mitjana, Anna
Navaridas Fernández de Bobadilla, RaúlNavaridas Fernández de Bobadilla, Raúl - ORCID ID
Vidal Sabanés, Maria
Perramon Güell, Aida
Yeramian Hakim, AndreeYeramian Hakim, Andree - ORCID ID
Felip Nogués, IsidreFelip Nogués, Isidre - ORCID ID
Eritja Sánchez, NúriaEritja Sánchez, Núria - ORCID ID
Egea Navarro, Joaquim
Encinas Martín, MarioEncinas Martín, Mario - ORCID ID
Matias-Guiu, XavierMatias-Guiu, Xavier - ORCID ID
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cc-by (c) Authors, 2022
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The extracellular matrix and the correct establishment of epithelial cell polarity plays a critical role in epithelial cell homeostasis and cell polarity. In addition, loss of tissue structure is a hallmark of carcinogenesis. In this study, we have addressed the role of extracellular matrix in the cellular responses to TGF-β. It is well known that TGF-β is a double-edged sword: it acts as a tumor suppressor in normal epithelial cells, but conversely has tumor-promoting effects in tumoral cells. However, the factors that determine cellular outcome in response to TGF-β remain controversial. Here, we have demonstrated that the lack of extracellular matrix and consequent loss of cell polarity inhibits TGF-β-induced apoptosis, observed when endometrial epithelial cells are polarized in presence of extracellular matrix. Rather, in absence of extracellular matrix, TGF-β-treated endometrial epithelial cells display features of epithelial-to-mesenchymal transition. We have also investigated the molecular mechanism of such a switch in cellular response. On the one hand, we found that the lack of Matrigel results in increased AKT signaling which is sufficient to inhibit TGF-β-induced apoptosis. On the other hand, we demonstrate that TGF-β-induced epithelial-to-mesenchymal transition requires ERK and SMAD2/3 activation. In summary, we demonstrate that loss of cell polarity changes the pro-apoptotic function of TGF-β to tumor-associated phenotype such as epithelial-to-mesenchymal transition. These results may be important for understanding the dual role of TGF-β in normal versus tumoral cells.
Journal or Serie
Scientific Reports, 2022, vol. 12, núm. 1