Overexpression of macrophage migration inhibitory factor induces angiogenesis and deteriorates prognosis after radical resection for hepatocellular carcinoma.
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 alpha-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.
Hira
Eiji
E
Department of Digestive and General Surgery, Faculty of Medicine, Shimane University, Izumo, Japan. ehira130@go3.enjoy.ne.jp
Ono
Takashi
T
Dhar
Dipok Kumar
DK
El-Assal
Osama N
ON
Hishikawa
Yoshitaka
Y
Yamanoi
Akira
A
Nagasue
Naofumi
N
D000368:Aged; D018952:Antigens, CD34 / Q000032:analysis; D014408:Biomarkers, Tumor / Q000032:analysis*; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000098:blood supply* / Q000737:chemistry* / Q000601:surgery; D018572:Disease-Free Survival; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006498:Hepatectomy; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000098:blood supply* / Q000737:chemistry* / Q000601:surgery; D008263:Macrophage Migration-Inhibitory Factors / Q000032:analysis*; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000378:metabolism*; D011237:Predictive Value of Tests; D011379:Prognosis; D014407:Tumor Cells, Cultured; D015854:Up-Regulation; D000509:alpha-Fetoproteins / Q000032:analysis
D018952:Antigens, CD34; D014408:Biomarkers, Tumor; D008263:Macrophage Migration-Inhibitory Factors; D000509:alpha-Fetoproteins