Hepatitis B virus X gene is implicated in liver carcinogenesis

Hepatitis B virus (HBV) is a small hepatotropic and highly species-specific enveloped DNA virus. The carcinogenicity of this virus has become focused on the X gene and its coded X protein. The X protein itself is unable to bind to DNA directly, but works as a potent transcriptional activator through multiple cis-acting elements and mediates several signal transduction cascades. Two regions of the X protein, aa.61–69 and aa.105–140, are found essential for the viral replication and expression as well. These functions interacting with transcription factors and signaling cascades are acting cooperatively to cause cell proliferation.Furthermore, the association of X protein with mitochondria causes loss of the mitochondrial membrane potential and subsequently causes cell death, the function of which is attributed to the aa.68–104 region of X protein. As a result, the X protein has two independent proliferative and cell death-promoting activities.Liver cancer has been shown to result from a series of mutations in specific oncogenes and tumor suppressor genes. In a recent study, X protein stimulates ROS generation in the mitochondria due to collapse of the membrane potential and increases the mutation frequency, that evokes malignant transformation. Inflammation as a result of HBV infection is concerned to cause DNA damage. In the past 10 years, the possibility that several viral proteins directly engaged in the DNA damage has increased to some extent. From an evolutionary viewpoint, it is noteworthy that several arrangement proteins have been found in viruses. Thus, there is some clue that a small amount of X protein acts as an arrangement protein for HBV replication dependent upon cellular DNA damage due to generated ROS as an amplified signal.