2624

The study of mucins as membrane localized glycoproteins that present a restricted pattern of expression in the human body is better defining normal tissues from their malignant counterparts. Mucin 17 (MUC17) is a large, membrane-anchored glycoprotein displayed primarily in the gastrointestinal tract where it likely serves a role in protection from this extra-cellular environment. We have found that MUC17 is aberrantly expressed in pancreatic tumor cells and tumor cell lines. No expression of MUC17 is detected in normal pancreas or in benign pancreatitis. It is therefore hypothesized that MUC17 is associated with pancreatic cancer, and its expression pattern may be a valuable marker for the diagnosis of this lethal disease. Understanding the biochemical and molecular events that lead to an altered MUC17 expression is highly warranted. The membrane-tethered mucin family members are synthesized as distinct forms including; membrane-bound, secreted, and deleted of the large mucin central domain. MUC17 is herein shown to give rise to two alternatively spliced mRNAs that code specifically for membrane-bound and secreted forms of the protein. The identification of both transcripts was shown in AsPC-1 (pancreatic adenocarcinoma) and Ls174T (colonic adenocarcinoma) cells lines which highly express MUC17. Evolutionary pressures are reported to have maintained clusters of related mucin genes at specific chromosomal loci including: 11p15.5 (secreted, gel forming - MUC2, -5AC, -5B, -6), 3q29 (soluble, non-gel forming MUC4, MUC20) and those under study at 7q22 (membrane-bound MUC3A/B, -12, -17) Radiation hybridization mapping has revealed that three GI track specific mucins (MUC3, MUC12, and MUC17) are clustered on the short arm of chromosome 7 within close proximity of each other. It stands to reason that some nature of co-regulatory control exists for these mucins and an altered expression of the clustered genes has implications in the diseased state. Therefore, expression of MUC17 was knocked-down in AsPC-1 and Ls174T cell lines. Clones were tested for MUC3, MUC12, and MUC17 expression alongside their parental cell lines to investigate phenotypic changes induced by the absence of MUC17 in the 7q22 cluster. Western blot and immunohistochemical analyses using rabbit polyclonal antibody generated against MUC17 confirmed MUC17 in pancreatic cancer cell lines, pancreatic adenocarcinoma, and colonic adenocarcinoma tissue sections. In conclusion, our new results provide the evidences for the existence of an alternative MUC17 transcript (which codes for a secreted form of the protein) and further show that MUC17 is aberrantly expressed in pancreatic adenocarcinoma where its exact implication will be determined in the near future.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]