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Int. J. Mol. Sci. 2018, 19(7), 2018; https://doi.org/10.3390/ijms19072018

TFF1 Promotes EMT-Like Changes through an Auto-Induction Mechanism

1
Department of Pharmacy, University of Salerno, 84084 Fisciano (SA), Italy
2
PhD Program in Drug Discovery and Development, University of Salerno, 84084 Fisciano (SA), Italy
*
Authors to whom correspondence should be addressed.
Received: 20 May 2018 / Revised: 29 June 2018 / Accepted: 5 July 2018 / Published: 11 July 2018
(This article belongs to the Special Issue Epithelial-Mesenchymal Transition (EMT))
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Abstract

Trefoil factor 1 (TFF1) is a small secreted protein expressed in the gastrointestinal tract where, together with the other two members of its family, it plays an essential role in mucosal protection and repair against injury. The molecular mechanisms involved in the protective function of all three TFF proteins are not fully elucidated. In this paper, we investigated the role of TFF1 in epithelial to mesenchymal transition (EMT) events. The effects of TFF1 on cellular models in normoxia and/or hypoxia were evaluated by western blot, immunofluorescence, qRT-PCR and trans-well invasion assays. Luciferase reporter assays were used to assess the existence of an auto-regulatory mechanism of TFF1. The methylation status of TFF1 promoter was measured by high-resolution melting (HRM) analysis. We demonstrate a TFF1 auto-induction mechanism with the identification of a specific responsive element located between −583 and −212 bp of its promoter. Our results suggest that TFF1 can regulate its own expression in normoxic, as well as in hypoxic, conditions acting synergistically with the hypoxia-inducible factor 1 (HIF-1α) pathway. Functionally, this auto-induction mechanism seems to promote cell invasion and EMT-like modifications in vitro. Additionally, exogenously added human recombinant TFF1 protein was sufficient to observe similar effects. Together, these findings suggest that the hypoxic conditions, which can be induced by gastric injury, promote TFF1 up-regulation, strengthened by an auto-induction mechanism, and that the trefoil peptide takes part in the epithelial-mesenchymal transition events eventually triggered to repair the damage. View Full-Text
Keywords: TFF1; gene regulation; invasion; epithelial to mesenchymal transition; hypoxia TFF1; gene regulation; invasion; epithelial to mesenchymal transition; hypoxia
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Romano, E.; Vllahu, M.; Bizzarro, V.; Belvedere, R.; Esposito, R.; Petrella, A.; Tosco, A. TFF1 Promotes EMT-Like Changes through an Auto-Induction Mechanism. Int. J. Mol. Sci. 2018, 19, 2018.

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