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

• Published in: Cancer 2015-12, Vol.121 (24), p.4348-4358
• Main Authors: Soutto, Mohammed, Chen, Zheng, Katsha, Ahmed M., Romero‐Gallo, Judith, Krishna, Uma S., Piazuelo, M. Blanca, Washington, M. Kay, Peek, Richard M., Belkhiri, Abbes, El‐Rifai, Wael M.
• Format: Article
• Language: English
• Subjects: Adenocarcinoma - genetics; Adenocarcinoma - immunology; Adenocarcinoma - microbiology; Animals; Carcinogenesis - genetics; Chemokine CXCL5 - immunology; gastric cancer; Gastric Mucosa - immunology; Gastric Mucosa - metabolism; Gastric Mucosa - microbiology; Helicobacter Infections - genetics; Helicobacter Infections - immunology; Helicobacter pylori; Humans; I-kappa B Kinase - metabolism; In Vitro Techniques; Inflammation; Interleukin-1beta - immunology; Mice; Mice, Knockout; nuclear factor κB (NF‐κB); Peptides - genetics; Phosphorylation; Real-Time Polymerase Chain Reaction; Receptors, Interleukin-4 - immunology; Stomach - immunology; Stomach - metabolism; Stomach - microbiology; Stomach Neoplasms - genetics; Stomach Neoplasms - immunology; Stomach Neoplasms - microbiology; Transcription Factor RelA - metabolism; trefoil factor 1 (TFF1); Trefoil Factor-1; Tumor Cells, Cultured; Tumor Necrosis Factor-alpha - immunology
• ISSN: 0008-543X; 1097-0142
• 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. Cancer 2015;121:4348–58. © 2015 American Cancer Society. Infection with Helicobacter pylori is the main risk factor for gastric cancer. This study demonstrates that trefoil factor 1 plays a critical role in antagonizing H. pylori–induced inflammation, a critical step in gastric carcinogenesis. Therefore, the reported frequent loss of trefoil factor 1 in gastric cancer could be a critical step in unleashing the proinflammatory oncogenic signaling of H. pylori in gastric tumorigenesis.