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Clinical significance of α-fetoprotein: involvement in proliferation, angiogenesis, and apoptosis of hepatocellular carcinoma


Dr Noboru Mitsuhashi, Section for Medical Nanotechniques, Research Center for Frontier Medical Engineering, Chiba University, 1-33, Yayoi-cho, Inage-ku, Chiba 263-8522, Japan. Email:


Background and Aim:  Hepatocellular carcinoma is one of the most common cancers. α-Fetoprotein is strongly expressed in most patients with hepatocellular carcinoma, and high levels of α-fetoprotein expression have been reported as an independent prognostic factor. However, there have been few reports on the reasons for poor prognosis.

Methods:  We analyzed the correlation between serum α-fetoprotein levels and clinicopathological findings in 37 hepatocellular carcinoma patients undergoing curative surgery. α-Fetoprotein mRNA expression in tissue samples was analyzed by quantitative reverse transcription–polymerase chain reaction (RT-PCR), while protein expression was assessed by immunohistochemistry. To assess the mechanistic correlations between α-fetoprotein and tumor progression, we further analyzed cell proliferation (Ki-67), angiogenesis (CD34), and apoptosis (TdT-mediated dUTP-biotin nick end labeling [TUNEL] assay).

Results:  Post-operative serum α-fetoprotein levels were correlated with disease-free and overall survival, and were an independent prognostic factor for survival. α-Fetoprotein expression, as assessed by immunohistochemistry, was strong and heterogeneous in hepatocellular carcinoma. Control livers did not express α-fetoprotein and there was weak expression of α-fetoprotein in adjacent regions in hepatocellular carcinoma patients. The Ki-67 labeling index in the high serum α-fetoprotein cases was significantly higher than in α-fetoprotein-negative cases (P = 0.042). The α-fetoprotein-positive cases also showed a significantly higher microvessel density than α-fetoprotein-negative cases (P = 0.035), whereas hepatocellular carcinoma without α-fetoprotein overexpression had a higher apoptotic index when compared to hepatocellular carcinoma with α-fetoprotein overexpression (P = 0.033).

Conclusion:  These results indicate that the poor prognosis associated with high α-fetoprotein is due to high cell proliferation, high angiogenesis, and low apoptosis.