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Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma

  1. Eiji Hira M.D.1,†,*,
  2. Takashi Ono M.D.1,
  3. Dipok Kumar Dhar M.D.1,
  4. Osama N. El-Assal M.D.2,
  5. Yoshitaka Hishikawa M.D.3,
  6. Akira Yamanoi M.D.1,
  7. Naofumi Nagasue M.D.1

Article first published online: 20 DEC 2004

DOI: 10.1002/cncr.20818

Issue

Cancer

Cancer

Volume 103, Issue 3, pages 588–598, 1 February 2005

Additional Information

How to Cite

Hira, E., Ono, T., Dhar, D. K., El-Assal, O. N., Hishikawa, Y., Yamanoi, A. and Nagasue, N. (2005), Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma. Cancer, 103: 588–598. doi: 10.1002/cncr.20818

Author Information

  1. 1

    Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Izumo, Japan

  2. 2

    Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland

  3. 3

    Department of Histology and Cell Biology, Nagasaki University School of Medicine, Nagasaki, Japan

  1. †

    Fax: 011 (81) 853202229

*Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Izumo 693-8501, Japan

Publication History

  1. Issue published online: 20 JAN 2005
  2. Article first published online: 20 DEC 2004
  3. Manuscript Accepted: 13 OCT 2004
  4. Manuscript Revised: 2 AUG 2004
  5. Manuscript Received: 13 APR 2004

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Keywords:

  • hypoxia;
  • recurrence;
  • endothelial cell;
  • hepatoma cell line;
  • microvessel density

Abstract

BACKGROUND

Macrophage migration inhibitory factor (MIF) is a pivotal cytokine that regulates inflammatory and immune responses. Recently, many investigators reported that MIF is expressed highly in several tumors, including hepatocellular carcinoma (HCC). However, the role of MIF in tumor angiogenesis and patient prognosis has not been examined in patients with HCC.

METHODS

The authors evaluated MIF expression in 56 samples of HCC by Western blot analysis, and the results were correlated with clinicopathologic factors and patient prognosis. MIF localization was determined by immunohistochemical methods, and the results were compared with tumor microvessel density (MVD), as assessed by anti-CD34 antibody. Furthermore, to validate the role of MIF in angiogenesis, both MIF expression during culture of HCC cells (using the Hep3B, HepG2, and Huh7 cell lines) under hypoxic condition and the angiogenic potential of recombinant MIF in an in vitro angiogenic model were examined.

RESULTS

Tumors with high MIF expression had high α-fetoprotein levels (P = 0.049) and frequent intrahepatic recurrence (P = 0.043). Immunohistochemical MIF scores had a significant correlation with MVD (P = 0.007). Patients who had tumors with high MIF expression levels had a significantly worse (P = 0.025) disease-free survival, and this finding remained significant as an independent prognostic factor in the multivariate analysis. Hep3B cells had high expression of MIF at 6 hours and 12 hours after hypoxic stress and exogenous MIF stimulated endothelial tube formation in in vitro angiogenesis.

CONCLUSIONS

The current findings suggest that MIF expression may play a pivotal role in the dismal prognosis of patients with HCC that may be attributable to the modulation of angiogenesis. Cancer 2005. © 2004 American Cancer Society.

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