Trefoil factor 1 expression suppresses Helicobacter pylori-induced inflammation in gastric carcinogenesis.

Soutto M, Chen Z, Katsha AM, Romero-Gallo J, Krishna US, Piazuelo MB, Washington MK, Peek RM, Belkhiri A, El-Rifai WM
Cancer. 2015 121 (24): 4348-58

PMID: 26372254 · PMCID: PMC4670586 · DOI:10.1002/cncr.29644

BACKGROUND - Infection with Helicobacter pylori, a high-risk factor for gastric cancer, is frequently associated with chronic inflammation through activation of nuclear factor κB (NF-κB). Trefoil factor 1 (TFF1) is a constitutively expressed protein in the stomach that has tumor-suppressor functions and plays a critical role in maintaining mucosal integrity. This study investigated the role of TFF1 in regulating the proinflammatory response to H. pylori infections.

METHODS - For in vitro studies, immunofluorescence, luciferase reporter assays, Western blots, and quantitative real-time polymerase chain reaction were performed to investigate the activation of NF-κB and its target genes in response to infections with H. pylori strains J166 and 7.13. In addition, Tff1-knockout (KO) and Tff1-wild-type mice were used for infections with the H. pylori strain called premouse Sydney strain 1.

RESULTS - The reconstitution of TFF1 expression in gastric cancer cells significantly suppressed H. pylori-mediated increases in NF-κB-p65 nuclear staining, transcriptional activity, and expression of proinflammatory cytokine genes (tumor necrosis factor α, interleukin 1β, chemokine [C-X-C motif] ligand 5, and interleukin 4 receptor) that were associated with reductions in the expression and phosphorylation of NF-κB-p65 and IκB kinase α/β proteins. The in vivo studies using the Tff1-KO mouse model of gastric neoplasia confirmed the in vitro findings. Furthermore, they demonstrated increases in chronic inflammation scores and in the frequency of invasive gastric adenocarcinoma in the Tff1-KO mice infected with H. pylori versus the uninfected Tff1-KO mice.

CONCLUSIONS - These findings underscore an important protective role of TFF1 in abrogating H. pylori-mediated inflammation, a crucial hallmark of gastric tumorigenesis. Therefore, loss of TFF1 expression could be an important step in H. pylori-mediated gastric carcinogenesis.

© 2015 American Cancer Society.

MeSH Terms (24)

Adenocarcinoma Animals Carcinogenesis Chemokine CXCL5 Gastric Mucosa Helicobacter Infections Helicobacter pylori Humans I-kappa B Kinase Inflammation Interleukin-1beta In Vitro Techniques Mice Mice, Knockout Peptides Phosphorylation Real-Time Polymerase Chain Reaction Receptors, Interleukin-4 Stomach Stomach Neoplasms Transcription Factor RelA Trefoil Factor-1 Tumor Cells, Cultured Tumor Necrosis Factor-alpha

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