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

• Published in: The Journal of clinical investigation 2011-05, Vol.121 (5), p.1753-1767
• Main Authors: Soutto, Mohammed, Belkhiri, Abbes, Piazuelo, M Blanca, Schneider, Barbara G, Peng, Dunfa, Jiang, Aixiang, Washington, M Kay, Kokoye, Yasin, Crowe, Sheila E, Zaika, Alexander, Correa, Pelayo, Peek, Jr, Richard M, El-Rifai, Wael
• Format: Article
• Language: English
• Subjects: Animals; Disease Progression; Gene Expression Profiling; Genetic aspects; Humans; I-kappa B Proteins - metabolism; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; NF-kappa B - metabolism; NF-KappaB Inhibitor alpha; Oligonucleotide Array Sequence Analysis; Peptides - metabolism; Phosphorylation; Physiological aspects; Risk factors; Stomach - metabolism; Stomach cancer; Stomach Neoplasms - metabolism; Transcription factors; Trefoil Factor-1; Tumor Necrosis Factor-alpha - metabolism; Tumor suppressor genes; Tumor Suppressor Proteins - metabolism
• ISSN: 0021-9738; 1558-8238
• 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.