| Mucins are large, multifunctional glycoproteins implicated in the protection and lubrication of epithelial tissues. The cellular production of mucins is optimally maintained by a host of elaborate and coordinated regulatory mechanisms, which are often disrupted in a variety of pathological conditions, including cancer. The overall objective of the studies presented in this dissertation was to evaluate the relevance of mucin deregulation to pancreatic cancer, the fourth leading cause of cancer-related death in the United States. Investigation of the profiles of mucin expression in a panel of human pancreatic tissues and cell lines revealed that the large transmembrane mucin, MUC4, was aberrantly expressed in a large number of pancreatic tumors and tumor cell lines. In contrast, this mucin remained undetectable in normal pancreatic and chronic pancreatitis tissues. Thus, these findings support a role of MUC4 as a pancreatic tumor marker with potential diagnostic implications.; We subsequently identified the molecular mechanisms regulating MUC4 expression in pancreatic tumor cells. The pleitropic cytokine, interferon-gamma (IFNgamma), was shown to stimulate MUC4 gene expression, via a novel signaling pathway involving upregulation of the signal transducer and activator of transcription 1 (STAT-1) as a key regulatory step. Moreover, we demonstrated that, in combination with retinoic acid (RA), a known inducer of MUC4 operating through the transforming growth factor beta (TGFbeta), IFNgamma exerted a potent synergistic effect on MUC4 stimulation. Interestingly, the molecular mechanisms underlying the observed synergism suggested a re-programming of the signaling pathways activated by IFNgamma and/or RA. Furthermore, we showed that MUC4, IFNgamma, TGFbeta, as well as several key inflammatory cytokines were differentially expressed in clinical specimens, suggesting a possible role of IFNgamma and RA/TGFbeta in regulating MUC4 expression in pancreatic tumor cells in vivo. In conclusion, the work presented in this dissertation establishes important clinical and molecular links between MUC4 and pancreatic cancer and exposes novel information regarding the regulation of this pancreatic tumor-associated mucin. |
