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Ultimately, for many patients the end result of a chronic context of decompensated cirrhosis, [224] and a strong
HBV infection is the development of HBV-associated relationship exists between chronic HBV infection and
HCC. While seven therapeutics are currently approved for cirrhosis. In fact, a recent cohort study demonstrated that
the treatment of chronic HBV, none has proven successful the cumulative lifetime risk of developing HBV-associated
at achieving an “absolute cure” or a complete loss of cirrhosis is 41.5% for chronically infected patients,
HBV DNA and a lifetime risk of development of HCC with a cumulative risk of developing HCC of 21.7%. [209]
equal to natural clearing of the infection. Five of these Therefore, establishing a clearer understanding of the
therapeutics are nucleoside analogs, designed to directly cellular mechanisms associated with the intermediate
inhibit the RT. The other two, standard and pegylated stages of chronic disease, particularly development of
interferon-α, function as antiviral cytokines, signaling cirrhosis, could enhance the overall understanding of
through the interferon receptor to activate the JAK-STAT causes of HBV-associated HCC.
pathway. [11,219] While generally effective at lowering viral
load, the fact that none of these anti-HBV therapies Numerous aspects of an HBV infection could be playing
is curative means these therapies must be life-long a role in the development of HCC. It is logical to assume
treatments, which eventually leads to the development that hepatotropic viruses such as HBV, which alter
of HBV mutants that are resistant to these therapies. hepatocyte physiology as part of, or a consequence of
Because of this, specific guidelines have been developed their replication, may disrupt normal hepatocyte and
for when to use antiviral therapy and which therapeutic overall liver functions. Many of these disruptions and
to use. [219] alterations, either through viral replication or activities
of viral proteins such as HBx, could be playing a role
HBV AND HCC in the development of downstream HBV-associated
HCC and have been extensively reviewed elsewhere
HCC, which accounts for 80-90% of all liver cancers, is one in the literature. For example, HBV has been shown
of the most common and most deadly cancers worldwide. to disrupt cell cycle regulation, [227,228] alter apoptotic
Globally, liver cancer is the sixth most common and second pathways, [229] alter hepatocyte metabolism, [33] and alter
deadliest cancer, with an incidence to mortality rate near miRNA expression and miRNA-mediated regulation. [230]
1. [222] Epidemiological studies have identified chronic HBV Many of these studies have focused on multiple cellular
infection of the liver as the leading risk factor for HCC signal transduction pathways, including those involving
development. [223,224] Despite the availability of a vaccine, Ras/mitogen-associated protein kinases (MAPK), [231]
350-500 million people worldwide are chronically infected mechanistic target of rapamycin (mTOR), [232] PI3K/
with HBV and, depending on age and route of infection, Akt, [86,233] and NFκB, [229] among many others. Each of
as many as 25% of these individuals could go on to these pathways and factors, while also important for HBV
develop HBV-associated HCC. [224,225] The number of cases replication, are main mediators of hepatocyte functions.
of HCC that are attributed to HBV will likely increase as As such, disruption can have a major impact on hepatocyte
occult infections become both better reported and better physiology, which has generated a considerable amount
understood. of interest in their potential role as mechanisms for the
development of HBV-associated HCC. The results of some
The molecular mechanisms that link a chronic HBV of these studies are summarized here.
infection to HCC development are incompletely
understood but are likely subtle considering that HBV- HBV and the cell cycle
associated HCC usually occurs in the context of a decades- As with many viruses, HBV must optimize the cellular
long chronic HBV infection. Studies have focused on three environment for viral replication. In the case of HBV,
main factors that may be involved in the development of this involves inducing hepatocytes to exit quiescence
HBV-associated HCC: chronic inflammation accompanied and enter into an active cell cycle, and the status of cell
by destruction and regeneration of hepatocytes, proliferation pathways can have a significant impact
consequences of HBV DNA integration into host genome, on HBV replication. For example, in primary rat
[91]
and the potential effects of HBV proteins such as hepatocytes, HBV moved cells from G into and through
0
HBx. [88,92,93,225,226] Some potential mechanisms that might G , but stalled progression before the hepatocytes
1
link an HBV infection to HCC development have already were able to reach S phase, and this regulation of the
been described above. Here we summarize additional cell cycle is required for HBV replication in primary rat
[85]
mechanisms that have been suggested to link a chronic hepatocytes. Studies in cell lines suggest a similar HBV-
HBV infection to the development of HCC. mediated regulation of cell cycle progression, with HBV
stalling progression of the cell cycle before entry into S
One particularly important intermediate aspect of phase in both Huh7 cells expressing HBV and the HBV-
a decades-long chronic HBV infection includes the expressing HepG2.2.15 cells. [234] Interestingly, studies
development of HBV-associated cirrhosis prior to HCC have also shown decreased proliferation of HepG2.2.15
development. [219] It is generally accepted that the majority, cells, in comparison to HepG2 cells, along with HBV-
potentially as much as 70-90%, of all HCC occurs in the mediated alteration of cell cycle regulators leading to a G1
Hepatoma Research | Volume 2 | July 1, 2016 175