Role of Inflammation in the Development and Progression of Pancreatic Cancer

我们首先验证了MIF有助于胰腺癌侵袭性并预测切除病例的疾病结局的假设，从而开始了我们的研究。与我们的假设一致，我们发现肿瘤中MIF mRNA表达的升高与PDAC切除病例的不良预后显著相关。这一观察结果使我们验证了MIF在上皮-间质转化（EMT）表型的获得中发挥作用，从而增强胰腺癌细胞的恶性潜能的假设。机制分析显示，MIF过表达降低了胰腺癌细胞系E-cadherin，升高了vimentin mRNA和蛋白水平，与EMT的分子特征一致。此外，过表达MIF显著提高了ZEB1/2，降低了miR-200b的表达，而shrna介导的抑制MIF增加了E-cadherin和miR-200b的表达，降低了胰腺癌细胞中ZEB1/2的表达。在过表达MIF的细胞中重新表达miR-200b恢复了上皮特征，E-cadherin的表达增加，ZEB1/2和vimentin的表达减少。MIF过表达细胞在体外侵袭能力和原位异种移植小鼠模型中肿瘤生长和转移显著增加，表明恶性潜能增加。这些结果清楚地支持了MIF在疾病侵袭性中的作用，表明其作为设计胰腺癌治疗新策略的候选治疗靶点的潜在有效性，并改善了预后（Funamizu等人，《国际癌症杂志》，Epub， 2012年7月23日）。我们正在进一步扩展我们的研究：a)检查mif诱导的EMT最接近的效应；b)研究不同MIF水平原发性胰腺癌细胞的转移潜能。

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.