The central hypothesis of this proposed study is that the MUC4 mucin contributes to the pathogenesis of pancreatic adenocarcinomas. Results of studies conducted in our laboratory and by other groups in the past few years have shown that MUC4 is overexpressed in pancreatic tumors compared to the normal pancreas. We have made significant progress in characterizing this biologically important molecule. The deduced structure of the encoded protein reveals traits that are typical of mucins and highlights the presence of multiple putative EGF domains, which may potentially confer important functions to the mature product. Furthermore, MUC4 is a membrane-anchored and highly glycosylated protein with an extended size that may exceed 2 pm over the cell surface, in which MUC4a is an extracellular mucin-type glycoprotein subunit, and MUC4 j3 is the transmembrane subunit. In consideration of the structural features of MUC4, as well as its frequent association with pancreatic adenocarcinomas, the need for an enhanced knowledge of the function(s) of this mucin cannot be overemphasized. During the previous funding period, we generated full-length MUC4 cDNA sequences, produced anti-MUC4 antibodies, and characterized a pancreatic tumor model (CDI8/HPAF) that showed regulated expression in vitro and in vivo. In the present proposal, our immediate objectives are to define the functions and regulatory mechanism(s) of MUC4 expression in pancreatic tumor cells. Our working hypothesis is that MUC4 is a multifunctional protein that promotes cell proliferation by signaling via its putative functional domains, and that confers anti-adhesive/adhesive properties to tumor cells owing to its unusually large size and extensive glycosylation. Additionally, we hypothesize that the regulation of MUC4 expression in pancreatic tumor cells is a complex process that entails the interplay of various biologically active factors such as IFN gamma and TGF beta 3. Specifically, we propose to: 1) Investigate if MUC4 expression contributes to the tumor growth and metastatic properties in pancreatic cancer cells by means of 'overexpression' and 'knockout' of the MUC4 gene. The roles of the structural components of MUC4 will also be examined. 2) Determine the mechanism(s) by which MUC4 expression can be regulated in pancreatic tumor cells. The CD18/HPAF pancreatic tumor cells will be used to investigate these mechanisms as MUC4 expression can be turned 'on' and 'off' in vitro and in vivo in these cells. Together, understanding the functions and mechanisms of regulated expression of MUC4 in pancreatic tumor cells can help to design diagnostics and therapeutic strategies for pancreatic cancer patients.
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