| First Author | Soutto M | Year | 2011 |
| Journal | J Clin Invest | Volume | 121 |
| Issue | 5 | Pages | 1753-67 |
| PubMed ID | 21490402 | Mgi Jnum | J:173945 |
| Mgi Id | MGI:5050584 | Doi | 10.1172/JCI43922 |
| Citation | Soutto M, et al. (2011) Loss of TFF1 is associated with activation of NF-kappaB-mediated inflammation and gastric neoplasia in mice and humans. J Clin Invest 121(5):1753-67 |
| abstractText | 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-alpha-mediated NF-kappaB activation through the TNF receptor 1 (TNFR1)/IkappaB kinase (IKK) pathway. Consistent with these mouse data, human gastric tissue samples displayed a progressive decrease in TFF1 expression and an increase in NF-kappaB activation along the multi-step carcinogenesis cascade. Collectively, these results provide evidence that loss of TFF1 leads to activation of IKK complex-regulated NF-kappaB transcription factors and is an important event in shaping the NF-kappaB-mediated inflammatory response during the progression to gastric tumorigenesis. |
