This proposal is to continue to study the structure, biosynthesis, immunology, and molecular biology of pancreatic cancer mucin. Mucin-associated antigens have been identified that are potentially useful for the detection, management, or even therapy of pancreatic cancers. One, SPan-1, has already proven useful in a clinical setting for the serological detection of pancreatic cancers. Another, ND2, shows promise as an aid to radio-imaging and might also be useful for immunotherapy. However, the mucins synthesized by pancreatic cancer cells are not well enough characterized to specify which combinations of oligosaccharide sequences and protein structures are cancer-associated and/or organ-specific. Although one mucin polypeptide, MUC1, has been shown to be present in some pancreatic cancer mucins, it is not yet known what other mucin polypeptides are present. We have identified cDNA clones for a novel mucin-like product, PUCK, but the complete sequence and the pattern of expression in pancreatic cancer, normal pancreas, and other tissues is unknown. The biosynthesis of MUC1 mucin in breast cancer cells has been extensively studied, but it is not known how processing differs in pancreatic cancer cells. How soluble mucin antigen is produced from membrane-bound MUC1 precursors (in either cell type) is unknown. Since the sequence of the gene is known, it is now possible to ask how the regulation of MUC1 expression differs between breast and pancreatic cancer cells. The structure of pancreatic cancer mucins will be investigated to determine i) what oligosaccharide structures are present that might be cancer-associated or organ-specific and ii) whether the cancer-associated antigens are present on the MUC1 protein or on other populations of mucin molecules. In studying mucin biosynthesis, we seek to i) establish the mechanisms of processing and secretion of soluble mucin and ii) determine whether the MUC1 protein is processed differently in pancreatic cancer cells as compared to breast cancer cells. Our studies of mucin immunology are designed to evaluate the potential usefulness of monoclonal antibody ND2 in i) radio-imaging and radioimmunotherapy of pancreatic cancers and ii)targeting of cytotoxic lymphocytes. The studies proposed on the molecular biology of mucin have as their objectives i) to complete the sequence of PUCK cDNAs and determine the pattern of expression of PUCK mRNA and protein, and ii) to identify pancreas-specific promoter regions in the MUC1 gene that might help to understand the expression of mucins in pancreatic cancers.
| Nogami, H; Ohmori, H; Li, J D et al. (1997) Sp1 protein contributes to airway-specific rat MUC 2 mucin gene transcription. Gene 198:191-201 |
