Abstract
The expression of TFF1 is frequently down-regulated in human gastric cancer whereas its knockout leads to the development of gastric adenomas and carcinomas in mouse models. The molecular mechanisms underlying the TFF1 tumor suppressor functions remain unclear. In this study, we demonstrate, using colony formation assay and Annexin V staining, that reconstitution of TFF1 expression in gastric cancer cell models suppresses cell growth and promotes cell death. Furthermore, using a tumor xenograft mouse model of gastric cancer, we demonstrated that reconstitution of TFF1 suppresses tumor growth in vivo. The results from PG13-luciferase reporter assay and Western blot analysis indicated that TFF1 promotes the expression and transcription activity of p53 protein. Further analysis using cycloheximide-based protein assay and quantitative real-time PCR data suggested that TFF1 does not interfere with p53 mRNA levels or protein stability. Alternatively, we found that the reconstitution of TFF1 down-regulates miR-504, a negative regulator of p53. Western blot analysis data demonstrated that miR-504 abrogates TFF1-induced p53 protein expression and activity. In conclusion, the in vitro and in vivo data demonstrate, for the first time, a novel mechanism by which the tumor suppressor functions of TFF1 involve activation of p53 through down-regulation of miR-504.
Highlights
TFF1 is a small-secreted protein that belongs to the family of trefoil peptides, and characterized by the presence of one to six cysteine-rich P domains [1]
To determine whether TFF1 suppresses growth in gastric cancer cells, we generated two gastric cancer cell lines, AGS and STKM2, stably overexpressing TFF1 or control empty vector pcDNA, and performed colony formation assay
These results clearly indicated that TFF1 stable expression significantly inhibits growth in gastric cancer cells
Summary
TFF1 (formerly known as pS2) is a small-secreted protein that belongs to the family of trefoil peptides, and characterized by the presence of one to six cysteine-rich P domains [1]. P53 activation involves stabilization of the protein, and enhancement of its DNA binding and transcriptional activity. MicroRNAs (miRNAs) are non-protein-coding sequences considered as a novel class of potential biomarkers or therapeutic targets, and are thought to regulate the expression of more than 70% of human genes [23]. MiR-34 was identified as a direct p53 target that regulates apoptosis, cell-cycle arrest, or senescence, contributing to tumor suppression [25,26,27]. We identified a novel mechanism by which TFF1 suppresses cell growth and induces apoptosis through activation of p53, by down-regulation of miR504, a negative regulator of p53, in gastric cancer cells
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