Hepatitis B type virus (HBV) is an old hepato oncogenic and hepatitis agent. Hepatitis B viral X protein (HBx)-induced malignant transformation requires the excess amounts of ATP level, inducing the extremely oxygen-deprived condition in the cancer tissues and vessels. To adapt, cells go to shift the hypoxic responsive state by altered hypoxia-responsive molecules such as HIF-1. In addition, tumors avoid or suppress immune recognition in the energy-deprived condition. The hypoxia-inducible factor-1α (HIF-1α) regulates MAP1, histone deacetylase and MAPK pathway. In the hypoxia, the HIF-1α interacts with HIF-1β, allowing DNA binding at the hypoxia response elements (HREs), while HBx binds with the nHLH/PAS domain of HIF-1α, preventing pVHL and HIF-1α binding capacity and degradation of HIF-1α protein. Recent work of Liu et al. [2013] demonstrated that HBx in hepatocellular carcinoma (HCC) tissues contained mutations, affecting the HBx transactivation capacity and C-terminal HBx mutation. In the HCC tissues, the HBx C-terminal mutation and HIF-1α expression were related and the different C-terminal mutations of HBx exhibit the different functionality of HIF-1α. The C-terminal region of amino acids 119-140 was important for the stability and transactivation, and the point mutations K130M/V131I enhance the functionality of HIF-1α, while C-terminal truncation diminish the HIF-1α function.