Page 96 - Read Online

Alqahtani et al. Hepatoma Res 2020;6:58 I http://dx.doi.org/10.20517/2394-5079.2020.49 Page 5 of 18

play a dominant role in the development of HCC in HBV-infected patients. In this light, elevated serum
levels of proinflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β
[55]
are typical hallmarks of HBV-infected patients . The long-lasting hepatic inflammation caused by the
host’s immune defense in response to CHB infection accelerates hepatocyte turnover, leading to increased
mutations. As such, the proinflammatory environment in the liver of HBV patients indirectly contributes to
[56]
the development of liver fibrosis, cirrhosis, and HCC progression .
In recent years, several studies have revealed an important role for micro-RNAs (miRNAs) in the
HBV-related tumorigenesis. The miRNAs are small noncoding RNAs of 20-25 nucleotides in length
that regulate the expression of certain target genes. For instance, HBeAg induces the expression of
macrophage miRNA-155, which leads to an accelerated liver injury through the increased production
of inflammatory cytokines (mediated by the targeting of BCL-6, SHIP-1, and SOCS-1) . A deregulated
[57]
miRNA expression (e.g., downregulation of miRNA-145 and upregulation of miRNA-224) occurs early
and accumulates overtime in the stages of HBV-associated multistep hepatocarcinogenesis . Apart from
[58]
the deregulated miRNA expression, HBV was also shown to cause other epigenetic changes and regulate
the expression of cellular oncogenes and tumor suppressor genes through a process of promotor hypo- or
[59]
hypermethylation .
HBV-encoded proteins also play a role in the inflammation processes that lead to the development of
HCC. In this respect, the HBV core protein and its splice variant HBeAg stimulate an immune response
[60]
in the host, resulting in an increased production of proinflammatory cytokines . A special role in
hepatocarcinogenesis has also been described for the HBx protein, per the model of transgenic mice
[61]
expressing HBx protein published in 1991 . Further research into the role of HBx revealed that this
protein transactivates binding sites for the transcription factors AP-1 and NF-κB, and it activates the p53
and β-catenin signaling pathways involved in chromatin remodeling. All these signaling cascades were
[62]
shown to be involved in the development of HCC (recently reviewed by Kanda et al. ). As such, HBx
[62]
seems to play an essential role in the transcriptional modulation that contributes to hepatocarcinogenesis .
Prevention of HBV-related HCC
In 2016, the WHO, along with other health authorities, launched a campaign for expanding the recognition
[63]
and treatment of HBV with the goal of eliminating viral hepatitis by 2030 . A package of high impact
interventions of high impact was designed, following modeling studies of hepatitis epidemiology, with the
anticipation of benefits conferred by articulated interventions like sanitation and even mass vaccination
against HBV of newborns. Indeed, early-in-life infection with HBV is the major risk factor fueling the
global reservoir of CHB, and it predisposes those individuals to HCC development. In WHO’s vision,
vaccination of all newborns is linked with the implementation of screening of blood donors and harm
reduction policies for people who inject drugs (i.e., exchange of sterile syringes and needles coupled with
[63]
opioid substitution therapies) . Strategies to interrupt vertical transmission of HBV through vaccination
are in place in almost all WHO member countries, yet only 39% of newborns received the HBV vaccine
globally . By 2015, however, 84% of all infants globally received the vaccine (WHO target for 2020 was
[64]
set at 90%). Over the last few years, the accumulated evidence showed that vaccination had substantially
contributed to shrinking the burden of HBV by over 30%. In China, campaigns of mass vaccination led
to a decline of HBsAg carrier state from approximately 90% in the eighties to 1% nowadays. In turn, this
averted 2.8-3.5 million future HBV-related deaths, of which the majority is associated with HCC . The
[64]
immune prophylaxis against HBV is long-lasting, although multiple long-term studies have demonstrated a
decline of protective serum anti-HBs levels (10 IU/mL) over time. While 60% of vaccinated people are anti-
HBs serum positive at year 20, more than 95% retain the ability to mount an anamnestic response after a
challenge dose at that time point . However, to achieve optimal rates of immunization (95%), all neonates
[65]
need to receive their first dose of the HBV vaccine as soon as possible after birth, preferably within 24 h.