Basic—Alimentary TractKlf4 Overexpression Activates Epithelial Cytokines and Inflammation-Mediated Esophageal Squamous Cell Cancer in Mice
Section snippets
Generation of ED-L2/Klf4 Mice
All animal studies were approved by the Institutional Animal Care and Use Committee at the University of Pennsylvania. To express Klf4 in esophageal epithelia, we subcloned the complete coding sequence of murine Klf4 into the pL2 plasmid (a gift from Dr Anil Rustgi, University of Pennsylvania), containing 782 base pairs of the Epstein–Barr virus ED-L2 promoter.18 ED-L2/Klf4 mice were back-crossed to C57BL/6 mice (Charles River, Wilmington, MA) for 10 generations and then used for experiments.
Results
To evaluate KLF4 function in esophageal epithelial homeostasis and carcinogenesis, we targeted Klf4 to esophageal epithelia using the Epstein–Barr virus ED-L2 promoter, which drives epithelial-specific expression in the tongue, esophagus, and squamous forestomach.18 Transgene expression was confirmed in the esophagus of 3 ED-L2/Klf4 transgenic lines by ribonuclease protection assays and immunohistochemistry (Supplementary Figure 1A–C). ED-L2/Klf4 mice were born at the appropriate Mendelian
Discussion
KLF4 has a well-established role in transcriptional regulation of proliferation and differentiation, and altered expression has been found in a number of cancers.5, 10, 11 Yet the function of KLF4 depends greatly on context.5 Recently, we showed that deletion of Klf4 in murine esophagus results in squamous cell dysplasia and delayed differentiation.22 Here, we identify a novel proinflammatory role for KLF4 via activation of the IKK/NF-κB pathway within epithelial cells. Interestingly, increased
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2021, Experimental Cell ResearchCitation Excerpt :Mice with mutations in P53 and Zinc deficiency showed metaplasia after administration of NMBA, while overexpression Cyclin D1 along with knockout of P53 developed invasive and metastatic ESCC [106,112]. Both models based on overexpression and deletion of KLF4 are compatible with the role of KLF4 in esophagus and induce epithelial cytokines, dysplasia, and inflammation-mediated squamous cell cancer at advanced age of mice, indicating inflammation-mediated carcinogenesis [113,114]. The EGFR overexpression in the basal and suprabasal cells of stratified squamous epithelium of mice using the ED-L2 promoter leads to squamous cell dysplasia [115].
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2021, Cellular and Molecular Gastroenterology and HepatologyCitation Excerpt :Interestingly, this increase of neutrophils also was observed along the different stages of ESCC pathogenesis in human patients.52 Moreover, we previously showed an increase in p65 NF-κB signaling and neutrophil recruitment in the early stages of chronic inflammation in a mouse model of ESCC.50 An important limitation to our scoring analyses of patient esophageal biopsy specimens is the limited availability of patient samples with precursor lesions of ESCC.
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2020, Biomedicine and PharmacotherapyCitation Excerpt :Since dysregulation of miR-1 can partake in the pathogenesis of inflammatory conditions, this miRNA might serve as a therapeutic targets in these disorders. In addition, Klf4 up-regulation is involved in the activation of epithelial cytokines and consequent development of esophageal squamous cell carcinoma in animal models [104]. Thus, miR-1-mediated regulation of KLF4 might be important in the carcinogenic processes as well.
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Conflicts of interest The authors disclose no conflicts.
Funding This work was supported by National Institutes of Health National Institute for Diabetes and Digestive and Kidney Diseases R01 DK069984 (J.P.K.) and by the University of Pennsylvania Center for Molecular Studies in Digestive and Liver Diseases (National Institutes of Health National Institute for Diabetes and Digestive and Kidney Diseases P30 DK050306) through the Morphology Core, the Molecular Biology Core, and the Transgenic and Chimeric Mouse Facility and by National Institutes of Health National Cancer Institute P01 CA098101.