Mechanisms underlying gene polymorphism in mitochondrial dysfunction of HCC

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The molecular mechanisms underlying hepatocarcinogenesis are very complex. Hepatocarcinogenesis is considered a multistep process involving subsequent gene mutations which control proliferation and/or apoptosis in the hepatocytes. Mitochondrial dysfunction-related genes are involved in the mechanisms underlying HCC. For instance, mitochondrial genes have been found to be differentially expressed in HBV X protein (HBx)-positive hepatoma cells (13, 14). Furthermore, three clones were shown to be human mitochondrial ATPase subunit 6 (mtATPase 6) (14). The HBx is a ubiquitous transactivator in HBV, which is essential for HBV replication in vivo. Mice expressing HBx in the liver may either develop HCC spontaneously (15) or display increased susceptibility to hepatocarcinogens (16). The introduction of HBx into HCC cell line Hep3B cells may induce apoptosis and sensitize Hep3B cells to TNFalpha-mediated cell killing; these processes may be accomplished via inhibition of Bcl-xL expression and subsequent promotion of cytochrome c release from mitochondria (17). In addition, the evidence gathered from epidemiological studies has demonstrated the connection between chronic HCV infection and the development of HCC (18,19). Additionally, in a mouse model of HCV-associated HCC, a deletion in mtDNA was reported (20). Taken together, these reports suggest the involvement of mitochondrial dysfunction-related genes in the pathogenesis of HCC. The function of mitochondria is associated with apoptosis, mitochondrial carriers, and metabolism; thus, we discuss the mechanisms underlying gene polymorphism in the mitochondrial dysfunction of HCC.