Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death, with an estimated more than 32,180 new cases and 31,800 deaths occurred each year in the United States. The five-year survival rate continues at 3-5%. The extreame mortality of PDACs is attributed to a lack of effective early detection methods and poor efficacy of existing therapies for advanced disease. PDAC exhibits a plethora of molecular alterations that include mutations in K-ras, p53, p16 and Smad4 genes, and overexpress multiple mitogenic growth factors and their tyrosine kinase receptors. It is likely that as-yet- unrecongonized genetic alterations also contribute to the carcinogenesis and progression of PDAC. Our long-term goal is to identify genetic alterations that contribtue to pancreatic cancer, so that early detection methods or novel preventive and therepeutic strategies can be developed. Kruppel-like factor 4 (KLF4) is a newly identified transcription factor that is associated with both tumor suppression and oncogenesis. Our recent preliminary data showed that aberrant up-regulation of KLF4 is aberrantly up-regulated in pancreatic cancers. However, enforced expression of wild-type KLF4 (wtKLF4) significantly suppressed pancreatic cancer cell growth in vitro and tumorigenesis in vivo. Intriguingly, we recently identified a sequence mutation in the KLF4 coding region in pancreatic cancer cell line, and cloned a new isoform of KLF4 (designated KLF4a) from human pancreatic cancer cell lines. Based on these preliminary findings, we hypothesized that there are genetic alterations in KLF4 in PDAC, the unidentified mutant KLF4 and the predominant KLF4a isoform have oncogenic function, and promote the development and progression of pancreatic cancer. To test our hypothesis, the experimental focus of this proposal is: 1) To identify sequence mutation(s) in KLF4 in pancreatic cancer tissues, and determine the function of mutant KLF4 in pancreatic cancer cells, and 2) To determine the biological significance, differential expression and regulation of KLF4a in pancreatic cancer. The results of this study will shed a new light on our understanding the molecular events that lead to the development and progression of pancreatic cancer. Such information obtained from this pilot study will provide a basis for further investigation into the development of early detection and effective treatment strategies for pancreatic cancer. ? ? ? ?
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