Mucin 17 (MUC17) is a new member of the mucin glycoprotein family. Mucins are important to cancer biology as they provide mechanisms that facilitate tumor growth, evasion, and metastasis. In general, they protect epithelial surfaces, but are known to be over expressed, mis-localized, and aberrantly displayed in a variety of cancers. Our work shows MUC17 is a novel protein displayed specifically in pancreatic adenocarcinoma compared to no expression in the normal pancreas or benign pancreatitis.

We have shown that the MUC17 gene encompasses 38,587 bp of genomic sequence, contains 13 exons and is transcribed as a 14,360 bp mRNA. We hypothesize that MUC17 is involved in the pathogenesis of pancreatic cancer, and report that the intergenic region (1,146 bp), between MUC12 and MUC17, possess both basal promoter and enhancer regulatory elements that are responsible for cell-specific regulation of MUC17. The cytokine TNF-α, and the growth factors TGFβ-1, TGFβ-2, and EGF are capable of activating transcription by increasing enhancer and/or basal promoter activities. Of particular interest is that a decrease in MUC17 expression is observed (below that of TNF-α or growth factor treatment alone) when the cytokine TNF-α is combined with (+EGF, +TGFβ-1, or +TGFβ-2). This suggests that a novel counter mechanism exists for down regulation of MUC17.

To understand the function of MUC17 in pancreatic cancer pathogenesis, stable MUC17 knock-down cell lines were created by expressing a MUC17-specific short hairpin (sh)RNA in AsPC-1 cells. In vitro and in vivo characterization showed MUC17 knock-down clones display increased motility. Orthotopic tumors of MUC17 shRNA cells showed a significant increase in total tumor weight, and in weight of secondary peritoneal masses. Our results demonstrate that loss of MUC17 in the AsPC-1 model promotes in vivo growth and metastasis. Microarray analyses revealed genes involved in cell adhesion, motility, WNT signaling, and (EGF)-like domain containing proteins are differentially expressed in the absence of MUC17. In conclusion, we have determined the structure of MUC17 gene, described its aberrant expression, investigated its regulation, and shown its function in preventing tumor growth. Altogether, MUC17 may be a protective membrane-bound mucin whose expression is associated with supressing tumor growth.