Expression of hypoxia-inducible factor 3α in hepatocellular carcinoma and its association with other hypoxia-inducible factors

The functional role of hypoxia-inducible factor (HIF)-3 alpha in the development of hepatocellular carcinoma (HCC) is not yet fully understood. The aim of the present study was to elucidate the association between HIF-3 alpha expression and the clinicopathological features as well as prognosis of HCC patients. In addition, we investigated the association between HIF-3 alpha expression and the expression of HIF-1 alpha and HIF-2 alpha in tumor tissues. The protein levels of HIF-3 alpha were determined using immunohistochemical analysis of paraffin sections of 126 paired HCC and peritumoral tissues. PLC/PRF/5 cells, a human HCC cell line, were transfected with HIF-1 alpha and HIF-2 alpha vectors and HIF-3 alpha mRNA and protein expression was detected using quantitative polymerase chain reaction and western blot analysis, respectively. The expression of HIF-3 alpha was upregulated in 46.0% (58/126) and downregulated in 42.9% (54/126) of tumor tissues, respectively, when compared to peritumoral tissues. HIF-3 alpha protein expression was not associated with peripheral blood vessel invasion, overall survival, or disease-free survival in HCC patients (P>0.05). In HCC tissues, the levels of HIF-3 alpha protein were positively correlated with HIF-2 alpha, but not with HIF-1 alpha expression in HCC tissues. HIF-3 alpha was upregulated in PLC/PRF/5 and Hep3B cells overexpressed with HIF-1 alpha or HIF-2 alpha. The hypoxic microenvironment of liver cancer did not lead to elevated HIF-3 alpha protein expression, indicating that HIF-3 alpha is regulated differently from HIF-1 alpha in vivo. The correlation between HIF-3 alpha and HIF-2 alpha expression at the cellular and tissue levels indicated that HIF-3 alpha may be a target gene of HIF-2 alpha. The hypoxic microenvironment did not lead to elevation of HIF-3 alpha protein expression in liver cancer; thus, HIF-3 alpha may be a target gene of HIF-2 alpha.