Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma

Naotake Funamizu, Chaoxin Hu, Curtis Lacy, Aaron Schetter, Geng Zhang, Peijun He, Jochen Gaedcke, Michael B. Ghadimi, Thomas Ried, Harris G. Yfantis, Dong H. Lee, Jeffrey Subleski, Tim Chan, Jonathan M. Weiss, Timothy C. Back, Katsuhiko Yanaga, Nader Hanna, H. Richard Alexander, Anirban Maitra, S. Perwez Hussain

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)785-794
Number of pages10
JournalInternational Journal of Cancer
Volume132
Issue number4
DOIs
StatePublished - Feb 15 2012

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Macrophage Migration-Inhibitory Factors
Epithelial-Mesenchymal Transition
Adenocarcinoma
Pancreatic Neoplasms
Cadherins
Vimentin
Neoplasms
gemcitabine
Messenger RNA
Chronic Pancreatitis
Heterografts
Small Interfering RNA
Epithelial Cells
Regression Analysis
Cytokines
Neoplasm Metastasis
Cell Line
Survival
Growth
Pharmaceutical Preparations

Keywords

  • EMT
  • MIF
  • miR-200
  • pancreatic cancer

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Medicine(all)

Cite this

Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. / Funamizu, Naotake; Hu, Chaoxin; Lacy, Curtis; Schetter, Aaron; Zhang, Geng; He, Peijun; Gaedcke, Jochen; Ghadimi, Michael B.; Ried, Thomas; Yfantis, Harris G.; Lee, Dong H.; Subleski, Jeffrey; Chan, Tim; Weiss, Jonathan M.; Back, Timothy C.; Yanaga, Katsuhiko; Hanna, Nader; Alexander, H. Richard; Maitra, Anirban; Hussain, S. Perwez.

In: International Journal of Cancer, Vol. 132, No. 4, 15.02.2012, p. 785-794.

Research output: Contribution to journalArticle

Funamizu, N, Hu, C, Lacy, C, Schetter, A, Zhang, G, He, P, Gaedcke, J, Ghadimi, MB, Ried, T, Yfantis, HG, Lee, DH, Subleski, J, Chan, T, Weiss, JM, Back, TC, Yanaga, K, Hanna, N, Alexander, HR, Maitra, A & Hussain, SP 2012, 'Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma', International Journal of Cancer, vol. 132, no. 4, pp. 785-794. https://doi.org/10.1002/ijc.27736
Funamizu, Naotake ; Hu, Chaoxin ; Lacy, Curtis ; Schetter, Aaron ; Zhang, Geng ; He, Peijun ; Gaedcke, Jochen ; Ghadimi, Michael B. ; Ried, Thomas ; Yfantis, Harris G. ; Lee, Dong H. ; Subleski, Jeffrey ; Chan, Tim ; Weiss, Jonathan M. ; Back, Timothy C. ; Yanaga, Katsuhiko ; Hanna, Nader ; Alexander, H. Richard ; Maitra, Anirban ; Hussain, S. Perwez. / Macrophage migration inhibitory factor induces epithelial to mesenchymal transition, enhances tumor aggressiveness and predicts clinical outcome in resected pancreatic ductal adenocarcinoma. In: International Journal of Cancer. 2012 ; Vol. 132, No. 4. pp. 785-794.
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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.",
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AU - Funamizu, Naotake

AU - Hu, Chaoxin

AU - Lacy, Curtis

AU - Schetter, Aaron

AU - Zhang, Geng

AU - He, Peijun

AU - Gaedcke, Jochen

AU - Ghadimi, Michael B.

AU - Ried, Thomas

AU - Yfantis, Harris G.

AU - Lee, Dong H.

AU - Subleski, Jeffrey

AU - Chan, Tim

AU - Weiss, Jonathan M.

AU - Back, Timothy C.

AU - Yanaga, Katsuhiko

AU - Hanna, Nader

AU - Alexander, H. Richard

AU - Maitra, Anirban

AU - Hussain, S. Perwez

PY - 2012/2/15

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N2 - 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.

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