Mechanisms of Pancreatic Carcinogenesis

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 DESCRIPTION (provided by applicant): Pancreatic cancer is the fourth most common cause of cancer-associated deaths in the U.S with a 5-year survival rate of only 7. High mortality rate is attributed to limitations in early diagnosis, aggressive disease progression, and lack of effective treatments. More than 90% of pancreatic cancer are invasive malignant neoplasms with glandular (ductal) differentiation, termed pancreatic ductal adenocarcinoma (PDAC). Pancreatic intraepithelial neoplasia (PanINs) are the most important type of precursors to PDAC, and tumorigenesis is believed to be a stepwise progression from low-grade PanINs to high-grade PanINs and then to invasive pancreatic neoplasia. Constitutively active mutations in Kirsten rat sarcoma viral oncogene homolog (KRAS) are some of the earliest mutations found in this progression, and they are present in over 90% of PDAC. Genomic studies in patient tumor sample support the model that mutation in KRAS is a major initiator of tumorigenesis while progression to carcinoma is accompanied by additional loss-of-function mutations in tumor suppressor genes. Krüppel-like factor 5 (KLF5) is a member in the Krüppel-like factor (KLF) family of transcription factors. KLF5 is important in the regulation of key cellular functions such as proliferation, differentiation, migration, and pluripotency. Depending on the cellular signaling context, KLF5 can be either a tumor suppressor or an oncogenic factor. Meta-analysis study of microarray data on differential expression of pancreatic tumor compared to normal tissue show a 2.5-fold overexpression in KLF5 mRNA. In vitro studies using human pancreatic cancer cell lines have shown that KLF5 may have oncogenic functions in pancreatic cancer cell lines. However, the role of KLF5 in pancreatic cancer in vivo has yet to be studied. My preliminary data show that PanINs from mice with mutant Kras have high expression of nuclear Klf5, which suggests that KLF5 may play a crucial and early role in regulating ADM process and PanIN formation. My overarching hypothesis is that KLF5 is critical for the formation of PanIN in Kras-induced tumorigenesis in vivo. To test this hypothesis, I propose the following Specific Aims: 1) To investigate whether KLF5 is necessary and sufficient for PanIN formation in vivo; 2) To elucidate the molecular mechanisms underlying the role of KLF5 in Kras-induced tumorigenesis. Through the proposed study, I wish to investigate the role and molecular mechanism of KLF5 as a crucial factor in process of ADM and PanIN formation during early tumorigenesis. The result of this study will be the basis for future investigations of KLF5 as a potential target for pancreatic cancer treatment.