The role of IFIT3 for the pro-inflammatory microenvironment of pancreatic cancer pathogenesis

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Ductal pancreatic adenocarcinoma (PDAC) belongs to the most common tumor-associated causes of death. Up to now, prognosis and survival of PDAC stay unfavorable. Recent research reports demonstrate a correlation between pancreatitis and the development of PDAC. Our preliminary results clearly show that IFIT3 (Interferon-Induced Protein With Tetratricopeptide Repeats 3) is a pro-carcinogenic protein for PDAC which is upregulated upon treatment with interferon-alpha. The aim of this proposal is to investigate whether IFIT3 acts as an interface between inflammation and PDAC carcinogenesis and partly responsible for the failure of interferon-alpha treatment of PDAC. Important aspects of this hypothesis have to be experimentally proven as follows:a) the role of IFIT3 as anti-apoptotic protein being neutralized via binding of the pro-apoptotic protein IFIT2,b) the participation of IFIT3 at the Sox9-IFIT3-STAT3-AP1 signal transduction cascade via its function as a scaffold protein, andc) the capability of IFIT3 to activate the production of pro-inflammatory cytokines leading to the phenomenon of local pseudoinflammation and establishment of a tumor growth supporting milieu.The results could contribute to a better understanding of the relationship between pancreatic carcinogenesis, pancreatitis, IFN-alpha-signal transduction and IFIT3 as pro-carcinogenic scaffold-protein