Loss of TFF1 promotes Helicobacter pylori-induced β-catenin activation and gastric tumorigenesis.

Soutto M, Romero-Gallo J, Krishna U, Piazuelo MB, Washington MK, Belkhiri A, Peek RM, El-Rifai W
Oncotarget. 2015 6 (20): 17911-22

PMID: 25980439 · PMCID: PMC4627225 · DOI:10.18632/oncotarget.3772

Using in vitro and in vivo models, we investigated the role of TFF1 in suppressing H. pylori-mediated activation of oncogenic β-catenin in gastric tumorigenesis. A reconstitution of TFF1 expression in gastric cancer cells decreased H. pylori-induced β-catenin nuclear translocation, as compared to control (p < 0.001). These cells exhibited significantly lower β-catenin transcriptional activity, measured by pTopFlash reporter, and induction of its target genes (CCND1 and c-MYC), as compared to control. Because of the role of AKT in regulating β-catenin, we performed Western blot analysis and demonstrated that TFF1 reconstitution abrogates H. pylori-induced p-AKT (Ser473), p-β-catenin (Ser552), c-MYC, and CCND1 protein levels. For in vivo validation, we utilized the Tff1-KO gastric neoplasm mouse model. Following infection with PMSS1 H. pylori strain, we detected an increase in the nuclear staining for β-catenin and Ki-67 with a significant induction in the levels of Ccnd1 and c-Myc in the stomach of the Tff1-KO, as compared to Tff1-WT mice (p < 0.05). Only 10% of uninfected Tff1-KO mice, as opposed to one-third of H. pylori-infected Tff1-KO mice, developed invasive adenocarcinoma (p = 0.03). These findings suggest that loss of TFF1 could be a critical step in promoting the H. pylori-mediated oncogenic activation of β-catenin and gastric tumorigenesis.

MeSH Terms (23)

Active Transport, Cell Nucleus Adenocarcinoma Animals beta Catenin Cell Line, Tumor Cell Proliferation Cell Transformation, Neoplastic Down-Regulation Gastric Mucosa Gene Expression Regulation, Neoplastic HEK293 Cells Helicobacter Infections Helicobacter pylori Host-Pathogen Interactions Humans Mice, Knockout Peptides RNA, Messenger Signal Transduction Stomach Neoplasms Transfection Trefoil Factor-1 Tumor Suppressor Proteins

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