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.
Highlights
Trefoil factor family (TFF) comprises three secreted peptides synthesized by mucous-producing cells: the gastric peptide pS2/Trefoil factor 1 (TFF1), the spasmolytic peptide (SP)/TFF2, and the intestinal trefoil factor (ITF)/TFF3
TFF1 is a secretory peptide mainly expressed in the gastric mucosa, where it represents a protective player against mucosal damage
Because TFF1 was reported to be overexpressed in migratory cells at the edge of the wound [46], we hypothesize that it could be involved in an epithelial to mesenchymal transition (EMT)-like mechanism of repair
Summary
Trefoil factor family (TFF) comprises three secreted peptides synthesized by mucous-producing cells: the gastric peptide pS2/TFF1, the spasmolytic peptide (SP)/TFF2, and the intestinal trefoil factor (ITF)/TFF3. They share a conserved structural motif of 38 or 39 amino-acid residues with six cysteines that, through disulphide bonds, form a three-looped structure, the so-called ‘trefoil’ domain. Found in breast cancer cells [3], in this tumor type, TFF1 was indicated as an oncogene in some papers [4,5] and as a predictive factor of positive response to hormone therapy in some others [6,7]. High levels of TFF1 were observed in different tumor tissues (colonic, pancreatic, and ovarian), in comparison with normal counterparts, correlated with the stimulation of cell survival, migration, invasiveness, and tumor dissemination [8,9,10]
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