The role of KLF5 in GI epithelial homeostasis and disease

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DESCRIPTION (provided by applicant): Kr¿ppel-like factor 5 (KLF5; IKLF; BTEB2), a zinc-finger transcription factor with pro-proliferative properties in vitro, is expressed in proliferating cells of gastrointestinal tract epithelia, including the basal cells of the esophagus. The interplay of these cells with the extracellular matrix (ECM) is critical to their function, and we have shown that Klf5 regulates proliferation in esophageal epithelial cells through the epidermal growth factor receptor (EGFR). In novel preliminary data, we demonstrate that Klf5 increases migration via the integrin- linked kinase (ILK) in primary esophageal keratinocytes in culture. Given these findings, Klf5 is an excellent candidate to orchestrate esophageal epithelial cell proliferation and migration in vivo. However, despite significant evidence of a pro-proliferative role for KLF5 in non-transformed epithelial cells, KLF5 inhibits proliferation, promotes anoikis, and decreases invasion of esophageal squamous cancer cells. KLF5 is also deleted or down-regulated in human breast and prostate cancers, as well as intestinal adenomas from mice and humans. In epithelial cancer cells, KLF5 protein undergoes more rapid degradation than in non- transformed epithelial cells. These findings suggest that extinction of KLF5 function may be important for carcinogenesis. In fact, KLF5 has been suggested to have tumor suppressive functions in human breast, prostate, esophageal, and colon cancers. This dichotomous role for KLF5 is not unique, as divergent functions have been reported for other factors, such as TGF?, Notch, and KLF4. Here, we will investigate the role of KLF5 in normal and transformed esophagus by testing the following hypotheses: (1) KLF5 is a critical regulator of proliferation, differentiation, and migration in transit amplifying cells of the esophagus; and (2) loss of KLF5 is a key step in malignant transformation in the esophagus. We will test these hypotheses through the following interrelated Specific Aims. In Specific Aim 1, we will investigate the role of KLF5 in esophageal epithelial homeostasis by: (a) evaluating integrin, integrin-linked kinase (ILK), and epidermal growth factor receptor (EGFR) signaling in non-transformed keratinocytes with overexpression or suppression of KLF5; (b) studying the transcriptional regulation of EGFR and ILK by KLF5; (c) examining mice with transgenic expression of Klf5 in the esophagus. In Specific Aim 2, we will determine the function of KLF5 during esophageal tumorigenesis by: (a) examining the regulation of the integrin, ILK, and EGFR pathways by KLF5 in transformed esophageal squamous cells; and (b) evaluating dysplasia and tumor formation in mice with transgenic expression of Klf5 in esophagus which have been treated with the carcinogen NMBA or crossed with ED-L2/cyclin D1 transgenic mice, an established genetic cancer model. Overall, an understanding of the pathways regulated by KLF5 in esophageal epithelia will provide a framework to understand the molecular events underlying esophageal diseases, both benign and malignant. PUBLIC HEALTH RELEVANCE: Diseases of the esophagus, such as gastroesophageal reflux disease and esophageal cancer, are among the most common ailments in the United States and throughout the world, and these diseases result from dysregulation of normal epithelial homeostasis. Thus, an appreciation of the molecular mechanisms, including the specific factors and complex signaling arrays, which govern normal esophageal proliferation and differentiation is critical to the understanding of esophageal diseases, both benign and malignant. The research proposed in this application aims to elucidate these factors and signaling pathways through studies of the key regulatory protein KLF5.