The Correlation of Expression Levels of HIF-1 and HIF-2 in Hepatocellular Carcinoma with Capsular Invasion, Portal Vein Tumor Thrombi and Patients' Clinical Outcome

Abstract

The roles of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in the development of hepatocellular carcinoma have not been fully elucidated. Here, we aim to uncover the relationship between the prognosis of hepatocellular carcinoma patients and the expression of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α in tumor tissues. The protein levels of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α were detected by immunohistochemistry on paraffin sections of 126 paired hepatocellular carcinoma tissue and peritumoral tissue samples. The mRNA levels of them were detected by quantitative real-time polymerase chain reaction. High expression of hypoxia-inducible factor-1α was found in 57.1% (72/126) of tumor specimens, compared with 5.6% (7/126) in peritumoral tissues, while high expression of hypoxia-inducible factor-2α was found in only 13.5% (17/126) of tumors, compared with 47.6% (60/126) of peritumoral tissues. There was high expression of hypoxia-inducible factor-1α protein in hepatocellular carcinoma tissues closely associated with capsular infiltration and portal vein invasion, and thus lower overall survival and disease-free survival of hepatocellular carcinoma patients (P < 0.05). No significant association has been found between the expression of hypoxia-inducible factor-2α protein and capsular infiltration, portal vein invasion, overall survival and disease-free survival (P > 0.05). However, patients with high expression of both hypoxia-inducible factor-1α and hypoxia-inducible factor-2α have a significantly worse outcome than patients with low expression of both hypoxia-inducible factor-1α and hypoxia-inducible factor-2α (P < 0.05). The discordant results on expression of hypoxia-inducible factor-1α and hypoxia-inducible factor-2α suggest that these two proteins are differentially regulated in vivo, thus reflecting distinctive protein expression and stabilization mechanisms. The association between hypoxia-inducible factor-1α expression and unfavorable outcome indicates the importance of using hypoxia-inducible factor-1α as a treatment target in hepatocellular carcinoma.