Klf4 overexpression activates epithelial cytokines and inflammation- mediated esophageal squamous cell cancer in mice

Mariepier Tetreault, Meilun Wang, Yizeng Yang, Jenna Travis, Qianchun Yu, Andres J. Kleinszanto, Jonathan P. Katz

Research output: Contribution to journalArticlepeer-review

38 Scopus citations

Abstract

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 Krppel-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-κBdependent 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.

Original languageEnglish (US)
Pages (from-to)2124-2134.e9
JournalGastroenterology
Volume139
Issue number6
DOIs
StatePublished - Dec 2010

Keywords

  • Esophagus
  • Keratinocyte
  • Transformation
  • Tumor Formation

ASJC Scopus subject areas

  • Hepatology
  • Gastroenterology

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