| Mucins, in general, are perceived as the biomolecules implicated in the protection and lubrication of epithelial surfaces. However, the recent realization that mucins can also function as signaling modulators and affect tumor cell phenotype has increased our interest in exploring their potential clinical usefulness. The MUC4 mucin, a transmembrane glycoprotein, is overexpressed in many epithelial carcinomas including pancreatic cancer. MUC4 is not expressed in the normal pancreas, while its aberrant expression is detected early in premalignant lesions exhibiting a correlative increase with disease advancement.; To elucidate the functions of MUC4 in pancreatic cancer pathogenesis, we generated MUC4 knock-down and ectopic expression models in MUC4-overexpressing and -null pancreatic cancer cell lines, respectively. The silencing of MUC4 was achieved by stable expression of a MUC4-specific short hairpin RNA in CD 18/HPAF, a highly metastatic pancreatic adenocarcinoma cell line. Inhibition of MUC4 expression suppressed the growth of pancreatic cancer cells. Our in vitro studies revealed that MUC4-associated increase in tumor cell growth resulted from both the enhanced proliferation and reduced apoptosis of pancreatic cancer cells. MUC4 expression was also associated with increased cell motility, invasiveness and changes in actin organization. The presence of MUC4 on the cell surface was shown to interfere with the tumor-cell extracellular matrix interactions, in part, by inhibiting the integrin-mediated cell adhesion. Ectopic expression of MUC4 in pancreatic cancer cells showed an enhanced growth of pancreatic cancer cells. However, no significant change in metastasis of pancreatic cancer cells was observed. Importantly, we identified galectin-3, a galactosidase binding protein, and HER2, a receptor tyrosine kinase, as novel interacting partners of MUC4. Furthermore, we demonstrate functional role of MUC4-galectin-3 interaction in potentiating tumor cell-endothelial cell interactions. Interestingly, we also observed that the silencing of MUC4 led to a correlative decrease in HER2 expression and its downstream (ERK and p38 MAPK) signaling. No changes, however, were detected in HER2 at the transcript level. This implies that MUC4 regulates the expression of HER2 by post-transcriptional mechanisms. In conclusion, our work provides experimental evidence for the multifaceted roles of MUC4 in the progression of pancreatic cancer. |
