Role of Inflammation in the Development and Progression of Pancreatic Cancer

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We started our investigation by first testing the hypothesis that MIF contributes to pancreatic cancer aggressiveness and predicts disease outcome in resected cases. Consistent with our hypothesis we found that an elevated MIF mRNA expression in tumors was significantly associated with poor outcome in resected cases of PDAC. This observation led us to test the hypothesis that MIF plays a role in the acquisition of epithelial-to-mesenchymal transition (EMT) phenotype and thereby enhancing malignant potential of pancreatic cancer cells. Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with molecular features of EMT. Furthermore, MIF-overexpression significantly increased ZEB1/2 and decreased miR-200b expression, while shRNA-mediated inhibition of MIF increased E-cadherin and miR-200b expression, and reduced the expression of ZEB1/2 in Pancreatic cancer cells. Re-expression of miR-200b in MIF overexpressing cells restored the epithelial characteristics, as indicated by an increase in E-cadherin and decrease in ZEB1/2 and vimentin expression. Indicative of an increased malignant potential, MIF over-expressing cells showed significant increase in their invasion ability in vitro, and tumor growth and metastasis in an orthotopic xenograft mouse model. These results clearly support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate therapeutic target for designing novel strategies for treatment of pancreatic cancer with improved outcome (Funamizu et. al., Int J Cancer, Epub, July 23, 2012). We are further extending our investigation to: a) Examine the most proximate effectors of MIF-induced EMT; b) Examine the metastatic potential of the primary pancreatic cancer cells with different levels of MIF.