Klf4 overexpression activates epithelial cytokines and inflammation-mediated esophageal squamous cell cancer in mice.
OBJECTIVE
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 Krüppel-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-α, CXCL5, G-CSF and IL-1α, within keratinocytes in an NF-κB-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
MP
Division of Gastroenterology, Department of Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Wang
Mei-Lun
ML
Yang
Yizeng
Y
Travis
Jenna
J
Yu
Qian-Chun
QC
Klein-Szanto
Andres J
AJ
Katz
Jonathan P
JP
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D002471:Cell Transformation, Neoplastic / Q000276:immunology; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000166:cytology / Q000276:immunology; D004938:Esophageal Neoplasms / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D004941:Esophagitis / Q000235:genetics / Q000276:immunology* / Q000503:physiopathology; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains
C000715468:Klf4 protein, mouse; D000090062:Kruppel-Like Factor 4; D051741:Kruppel-Like Transcription Factors
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