Background & Aims Klf4 (Krüppel-like factor 4; GKLF) is a DNA-binding transcriptional regulator highly expressed in skin and gastrointestinal epithelia, specifically in regions of cellular differentiation. Homozygous null mice for Klf4 die shortly after birth from skin defects, precluding their analysis at later stages. The aim of this study was to analyze the function of Klf4 in keratinocyte biology and epithelial homeostasis in the adult by focusing on the squamous lined esophagus. Methods Using the ED-L2 promoter of Epstein-Barr virus to drive Cre, we obtained tissue specific ablation of Klf4 in the squamous epithelia of the tongue, esophagus, and forestomach. Results Mice with loss of Klf4 in esophageal epithelia survived to adulthood, bypassing the early lethality. Tissue-specific Klf4 knockout mice had increased basal cell proliferation and a delay in cellular maturation; these mice developed epithelial hypertrophy and subsequent dysplasia by 6 months of age. Moreover, loss of Klf4 in vivo was associated with increased expression of the pro-proliferative Klf5, and Klf4 downregulated Klf5 both transcriptionally and post-transcriptionally. Using gene expression profiling, we also showed decreased expression of critical late-stage differentiation factors and identified alterations of several genes important in cellular differentiation. Conclusions Klf4 is essential for squamous epithelial differentiation in vivo and interacts with Klf5 to maintain normal epithelial homeostasis.

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 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.

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