Growth Regulatory Mechanisms of KLF in Barrett's Epithelium

Project: Research project

Project Details

Description

Barrett's esophagus is a pre-neoplastic condition in which the normal squamous epithelium is replaced by
metaplastic columnar epithelium in the lower esophagus as a result of chronic esophageal reflux injury. This
reflux related injury has been implicated in the development of highly lethal adenocarcinoma in Barrett's
mucosa which is one of the most rapidly increasing cancers. Thus, understanding the mechanisms of
neoplastic transformation in Barrett's esophagus is of great importance. Contents of reflux activate PGE2
synthesis in Barrett's esophagus. We and others have noted that high levels of PGE2 promote neoplastic
transformation in Barrett's esophagus. However, the details of the underlying molecular mechanisms remain
unclear. The rate-limiting step in the PGE2 synthesis pathway is the release of arachidonic acid from the
membrane phospholipids by phospholipase A2, particularly cPLA2-a (cytosolic PLA2-a). The promoter
region of cPLA2-a has GC-rich regions to which the members of SP/KLF (stimulatory protein/ Kruppel like
factors) family of transcription factors can bind.
In preliminary studies, we made the following novel observations that 1) KLF11 acts as a represser of the
cPLA2-a promoter activity and decreases PGE2 production, 2) KLF11 down-regulates the growth of
malignant Barrett's epithelial cells, 3) the growth inhibitory effect of KLF11 is associated with up-regulation of
the expression growth regulatory genes in malignant Barrett's epithelial cells, and 4) there is pronounced
loss of KLF11 expression during the progression of neoplasia in Barrett's esophagus. Based on these
observations, our CENTRAL HYPOTHESIS is that KLF11 behaves as a tumor suppressor by a dual
mechanism involving inhibition of PGE2 synthesis by repressing cPLA2a promoter activity and also via
regulation of genes involved in the cell cycle and apoptosis in Barrett's epithelium. To assess this we will use
three specific aims. FIRST, we will examine the molecular mechanisms of KLF11-mediated inhibition of
PGE2 pathway in Barrett's epithelium. SECOND, we will assess the PGE2 dependent and independent
cellular mechanisms of the tumor suppressive role of KLF11 in Barrett's epithelium. THIRDLY, we will
determine the in vivo relevance of KLF11 on the neoplastic transformation in Barrett's mucosa by using KLF-
/- mice with reflux. This mechanistic, hypothesis-driven study will use state-of-the art methodology and has
significant translational relevance. In this KO8 Mentored Clinical Scientist Development Award, I will acquire
a comprehensive, in depth knowledge of molecular cell biology and biochemical techniques to
mechanistically answer the pathophysiological questions. These skills will allow me to launch a productive
independent investigative career. The mentoring environment at Mayo Clinic is conducive to successfully
accomplish these goals.
StatusNot started

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