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  • The mitochondrial haplotype constitutes the genetic backgrou


    The mitochondrial haplotype constitutes the genetic background for host cells invaded by HBV. A comprehensive study on peripheral blood, tumor and/or adjacent non-tumor tissue from 49 HBV-HCC patients and 38 normal people revealed that people with mtDNA haplogroup M may have increased likelihood of onset of HCC [20]. On the other hand, it has been demonstrated that high cytosolic calcium is essential for HBV DNA replication [21], which involves HBx-mediated activation of Pyk2/FA kinase and JNK- and MAPK-associated signal transduction pathways [22]. Mitochondrial calcium uptake plays an important role in sustaining elevated levels of cytosolic calcium [23], [24]. In association with mitochondrial permeability transition pore, HBx elevates mitochondrial dependent calcium signaling and stimulates HBV replication [25], [26].
    HCV Hepatitis C virus (HCV) is a positive-sense single-stranded RNA virus with a diameter of 55–65nm. It belongs to the family of flaviviridae [27]. It is estimated that 3% of the world's population is infected with HCV, and most of them are unidentified [28]. Like HBV, HCV is also a major risk factor for HCC. The incidence of HCC with HCV is increasing in many countries including the United States [29]. HCV has a 9.6kb genome, composed of 5′ and 3′ non-translated regions flanking an open reading frame (ORF) encoding a large polyprotein. The HCV genome encodes 10 individual membrane-associated viral proteins which are divided into structural proteins including core protein, envelope 1 (E1) and envelope 2 (E2), and non-structural proteins, including p7 polypeptide, NS2, NS3, NS4A, NS4B, NS5A and NS5B proteins [30]. HCV core protein, a component of the viral nucleocapsid, plays a critical role in virus growth and differentiation [31]. NS3 complex with NS4A, in the form of the NS3-4A polyprotein, acts as a cofactor of the proteinase. NS4B protein induces the formation of a membranous web which facilitates the replication, assembly and release of HCV. NS5A was reported to cause aberrant and persistent G2/M-phase entry, thereby sustaining proliferative signaling [32]. The HCV core protein localizes both to ER and the mitochondrial outer membrane via a region spanning Fulvestrant (ICI 182,780) 112 to 152 [33]. The core protein induces a specific inhibition of complex I, which adapts mitochondria for hypoxia and enhances ROS production at the same time [34]. Meanwhile, the core protein facilitates ER Ca release and increases mitochondrial Ca uptake. Such calcium signaling modulation increases mitochondrial ROS production and mitochondrial permeability transition as well as decreasing MMP [35]. HCV infection has also been shown to stimulate mitophagy through up-regulating Parkin and PINK1 proteins. It also triggers Parkin translocation to mitochondria and induces mitochondrial perinuclear clustering [36]. The NS3 and NS4A complex NS3-4A protein, a serine protease, inhibits MAVS by cleaving it from the outer mitochondrial membrane and preventing the formation of MAVS signaling complex for antiviral functions [37]. In addition, HCV NS4B initiates the disruption of MMP and release of cytochrome c which in turn activates the caspase cascade and induces apoptosis [38]. NS5A modulates apoptosis by regulating cytochrome c and Bax [39].
    HPV The Human Papillomavirus (HPV) is small, double stranded circular DNA virus with a diameter of 45–55nm [40]. It has been well established that genital tract epithelial infection with high-risk types of HPV causes cervical cancer (CC) [41]. At the same time, high-risk HPV DNA has also been detected in 99.7% of CC patients [42]. HPV belongs to the papillomavirus family, of which over 170 genotypes have been characterized [40]. HPV16 and 18 is the most common high-risk HPV [43], [44], [45]. The HPV genome is about 8.0kb, and it encodes 3 overlapping open reading frames designated as long control region (LCR), early genes region (encoding early regulatory proteins, such as E2, E4, E6, and E7), and late genes region (encoding capsid proteins L1 and L2). E6 [46] and E7 [47] are essential for the production of HPV DNA synthesis proteins. In HPV-associated CC, E6 and E7 are always expressed [48], [49], while E2 and E4 are not expressed [50], [51]. There is also a spliced mRNA, E1^E4, which encodes five amino acids from the E1 ORF spliced to the protein encoded by the E4 ORF, which binds and collapses the cytokeratin network and facilitates release of the virus from cells [52].