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Tetreault MP , Wang ML , Yang Y , Travis J , Yu QC , Klein-Szanto AJ , Katz JP
Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice
Gastroenterology. 2010 Dec;139(6) :2124-2134 e9
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BACKGROUND & AIMS: Esophageal squamous cell cancer accounts for more than 90% of cases of esophageal cancers. Its pathogenesis involves chronic epithelial irritation, although the factors involved in the inflammatory process and the mechanisms of carcinogenesis are unknown. We sought to develop a mouse model of this cancer. METHODS: We used the ED-L2 promoter of Epstein-Barr virus to overexpress the transcriptional regulator Kruppel-like factor 4 (Klf4) in esophageal epithelia of mice; we used mouse primary esophageal keratinocytes to examine the mechanisms by which KLF4 induces cytokine production. RESULTS: KLF4 was an epithelial-specific mediator of inflammation; we developed a new mouse model of esophageal squamous dysplasia and inflammation-mediated squamous cell cancer. KLF4 activated a number of proinflammatory cytokines, including TNF-alpha, CXCL5, G-CSF and IL-1alpha, within keratinocytes in an NF-kappaB-dependent manner. KLF4 was not detected in proliferating or cancer cells, indicating a non-cell autonomous effect of KLF4 on proliferation and carcinogenesis. CONCLUSIONS: KLF4 has distinct functions in carcinogenesis; upregulation of Klf4 specifically in esophageal epithelial cells induces inflammation. This mouse model might be used to determine the molecular mechanisms of esophageal squamous cell cancer and inflammation-mediated carcinogenesis.
Tetreault, Marie-Pier Wang, Mei-Lun Yang, Yizeng Travis, Jenna Yu, Qian-Chun Klein-Szanto, Andres J Katz, Jonathan P P01 CA098101/CA/NCI NIH HHS/United States P30 DK050306/DK/NIDDK NIH HHS/United States R01 DK069984/DK/NIDDK NIH HHS/United States Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't United States Gastroenterology Gastroenterology. 2010 Dec;139(6):2124-2134.e9.