Molecular Characterization of Trefoil factor 1 in Gastric Carcinoma

Abstract

The trefoil factors (TFF) are a cluster of three genes, which contain a characteristic trefoildomain. TFF1 is secreted from the gastric mucosa and is involved in the maintenance and restitution of epithelium of the gastrointestinal tract. TFF1 promotes cell migration and invasion, prevents anoikis and has also been associated with angiogenesis. Studies have demonstrated that an increase in the expression of TFF1 in mammary carcinoma enhances oncogenic properties, but the effector molecule(s) mediating these functions have not been identified yet. Some studies have suggested that TFF1 may be a tumour suppressor gene in gastric carcinoma. However, a few other studies have demonstrated that TFF1 decreases apoptosis, increases cell migration and invasionof gastric cancer. Herein, I demonstrate the oncogenic function of TFF1 in gastric carcinoma cells. Through this research, it was found that forced expression of TFF1 increased the total cell number in suspension culture, increased cell survival, increased cell progression in gastric MKN45 cells, but not in the AGS cells. TFF1 enhanced anchorage-independent growth with increased cell migration and invasion in both cell types. Moreover, forced expression of TFF1 increased the tumour formation abilities of MKN45 cell line in xenograft models and not in the AGS cells.Conversely, depletion of TFF1 by RNA interference (RNAi) in gastric carcinoma cells significantly reduced anchorage-independent growth, migration and invasion. Furthermore, neutralization of secreted TFF1 by polyclonal antibody decreased gastric carcinoma cell viability in vitro and increased apoptosis in both of the cell lines. Further, I demonstrated forced expression of TFF1 in AGS and MKN45 cells increased VEGF-A expression and promoted tumour angiogenesis in the gastric carcinoma cells through increased VEGF-A expression. Moreover, I demonstrated that the forced expression of TFF1 increased endothelial cell tube formation, proliferation, survival, migration and invasion. TFF1 decreased apoptosis in vitro.Thus, my study strongly suggests that the functional antagonism of TFF1 would be a useful strategy in the therapeutic intervention of gastric carcinoma.