Loss of TFF1 is associated with activation of NF-κB-mediated inflammation and gastric neoplasia in mice and humans.

Soutto M, Belkhiri A, Piazuelo MB, Schneider BG, Peng D, Jiang A, Washington MK, Kokoye Y, Crowe SE, Zaika A, Correa P, Peek RM, El-Rifai W
J Clin Invest. 2011 121 (5): 1753-67

PMID: 21490402 · PMCID: PMC3083788 · DOI:10.1172/JCI43922

Trefoil factor 1 (TFF1) is a tumor suppressor gene that encodes a peptide belonging to the trefoil factor family of protease-resistant peptides. Although TFF1 expression is frequently lost in gastric carcinomas, the tumorigenic pathways this affects have not been determined. Here we show that Tff1-knockout mice exhibit age-dependent carcinogenic histological changes in the pyloric antrum of the gastric mucosa, progressing from gastritis to hyperplasia, low-grade dysplasia, high-grade dysplasia, and ultimately malignant adenocarcinoma. The histology and molecular signatures of gastric lesions in the Tff1-knockout mice were consistent with an inflammatory phenotype. In vivo, ex-vivo, and in vitro studies showed that TFF1 expression suppressed TNF-α-mediated NF-κB activation through the TNF receptor 1 (TNFR1)/IκB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-κB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-κB transcription factors and is an important event in shaping the NF-κB-mediated inflammatory response during the progression to gastric tumorigenesis.

MeSH Terms (19)

Animals Disease Progression Gastric Mucosa Gene Expression Profiling Humans I-kappa B Proteins Inflammation Mice Mice, Inbred C57BL Mice, Knockout NF-kappa B NF-KappaB Inhibitor alpha Oligonucleotide Array Sequence Analysis Peptides Phosphorylation Stomach Neoplasms Trefoil Factor-1 Tumor Necrosis Factor-alpha Tumor Suppressor Proteins

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