title: Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma.
abstract: MIF is a proinflammatory cytokine and is implicated in cancer. A higher MIF level is found in many human cancer and cancer-prone inflammatory diseases, including chronic pancreatitis and pancreatic cancer. We tested 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. Multivariate Cox-regression analysis further showed that MIF is independently associated with patients' survival (HR = 2.26, 95% CI = 1.17-4.37, p = 0.015). Mechanistic analyses revealed that MIF overexpression decreased E-cadherin and increased vimentin mRNA and protein levels in pancreatic cancer cell lines, consistent with the features of epithelial-to-mesenchymal transition (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 Panc1 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. A reduced sensitivity to the chemotherapeutic drug, gemcitabine, occurred in MIF-overexpressing cells. 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 support a role of MIF in disease aggressiveness, indicating its potential usefulness as a candidate target for designing improved treatment in pancreatic cancer.
authors: Laboratory of Human Carcinogenesis, Center for Cancer Research, NCI, NIH, Bethesda, MD.
authors: Naotake
authors: N
authors: Funamizu
authors: Chaoxin
authors: C
authors: Hu
authors: Curtis
authors: C
authors: Lacy
authors: Aaron
authors: A
authors: Schetter
authors: Geng
authors: G
authors: Zhang
authors: Peijun
authors: P
authors: He
authors: Jochen
authors: J
authors: Gaedcke
authors: Michael B
authors: MB
authors: Ghadimi
authors: Thomas
authors: T
authors: Ried
authors: Harris G
authors: HG
authors: Yfantis
authors: Dong H
authors: DH
authors: Lee
authors: Jeffrey
authors: J
authors: Subleski
authors: Tim
authors: T
authors: Chan
authors: Jonathan M
authors: JM
authors: Weiss
authors: Timothy C
authors: TC
authors: Back
authors: Katsuhiko
authors: K
authors: Yanaga
authors: Nader
authors: N
authors: Hanna
authors: H Richard
authors: HR
authors: Alexander
authors: Anirban
authors: A
authors: Maitra
authors: S Perwez
authors: SP
authors: Hussain
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics; D003841:Deoxycytidine / Q000031:analogs & derivatives / Q000494:pharmacology; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D008263:Macrophage Migration-Inhibitory Factors / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D011379:Prognosis; D034622:RNA Interference; D014183:Transplantation, Heterologous; D000093542:Gemcitabine
chemical_list: D000964:Antimetabolites, Antineoplastic; C533896:MIRN200 microRNA, human; D008263:Macrophage Migration-Inhibitory Factors; D035683:MicroRNAs; D003841:Deoxycytidine; D000093542:Gemcitabine