Abstract
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.
Keywords:
Helicobacter pylori; TFF1; gastric cancer; ß-catenin.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Active Transport, Cell Nucleus
-
Adenocarcinoma / genetics
-
Adenocarcinoma / metabolism*
-
Adenocarcinoma / microbiology
-
Adenocarcinoma / pathology
-
Animals
-
Cell Line, Tumor
-
Cell Proliferation
-
Cell Transformation, Neoplastic / genetics
-
Cell Transformation, Neoplastic / metabolism*
-
Cell Transformation, Neoplastic / pathology
-
Down-Regulation
-
Gastric Mucosa / metabolism*
-
Gastric Mucosa / microbiology
-
Gastric Mucosa / pathology
-
Gene Expression Regulation, Neoplastic
-
HEK293 Cells
-
Helicobacter Infections / complications
-
Helicobacter Infections / genetics
-
Helicobacter Infections / metabolism*
-
Helicobacter Infections / microbiology
-
Helicobacter Infections / pathology
-
Helicobacter pylori / metabolism
-
Helicobacter pylori / pathogenicity*
-
Host-Pathogen Interactions
-
Humans
-
Mice, Knockout
-
Peptides / deficiency
-
Peptides / genetics
-
Peptides / metabolism*
-
RNA, Messenger / metabolism
-
Signal Transduction
-
Stomach Neoplasms / genetics
-
Stomach Neoplasms / metabolism*
-
Stomach Neoplasms / microbiology
-
Stomach Neoplasms / pathology
-
Transfection
-
Trefoil Factor-1
-
Tumor Suppressor Proteins / deficiency
-
Tumor Suppressor Proteins / genetics
-
Tumor Suppressor Proteins / metabolism*
-
beta Catenin / genetics
-
beta Catenin / metabolism*
Substances
-
CTNNB1 protein, human
-
CTNNB1 protein, mouse
-
Peptides
-
RNA, Messenger
-
TFF1 protein, human
-
Tff1 protein, mouse
-
Trefoil Factor-1
-
Tumor Suppressor Proteins
-
beta Catenin