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Page 2 of 15 Song et al. Hepatoma Res 2020;6:27 I http://dx.doi.org/10.20517/2394-5079.2020.05

decades due to therapy advancement and control of etiology. In contrast, incidence and mortality rates in
North America have been increasing since 1978, for which the main reasons are cumulative emergence of
new risk factors and lack of efficient therapy strategies.

HCC is prominently induced by chronic hepatitis B virus (HBV)/hepatitis C virus (HCV) infection,
alcoholic or nonalcoholic fatty liver disease, aflatoxin intake and parasitic infection, the incidence of which
are related with geographic variance. About 80% of HCC arises from persistent HBV infection in Asia-
Pacific and Africa countries, while non-alcoholic fatty liver disease (NAFLD) is the major contributor in
North America, followed by HCV infection. The direct-acting antiviral therapy with high rates of safety and
[1,2]
sustained virologic response (> 95%), is considered as the contributing factor for eliminating HCV , which
helps decrease the pathogenesis of HCC. However, HBV-associated HCC remains to be a global problem,
because current nucleos(t)ide analogue therapy functionally reduces HBsAg level and suppresses HBV DNA
[3,4]
but fails to control remission . Since obesity has emerged as a new global burden, NAFLD, which is one of
the most common metabolic syndrome manifesting in liver with estimated prevalence of 20%~30% in many
[5-9]
countries, will rank as the leading cause of HCC in future decades .

Although patients diagnosed with early stage of HCC undergo surgical resection or radiofrequency ablation
[10]
for curative intent, up to 70% of them are susceptible to recurrence within 5 years . During the last decades,
conventional chemotherapy and combination of transarterial chemoembolization and sorafenib have been
developed for patients at intermediate and advanced stages, however, therapy efficacy and adverse effects
should be further assessed. Although sorafenib has been approved for treatment of HCC, the tyrosine kinase
[11]
inhibitors-induced adverse events and drug resistance still remain an issue during clinical management .
Therefore, more novel target agents and immunotherapies are being investigated and incorporated to achieve
better outcomes [12,13] . Here, this review mainly discusses the current progress in molecular and cellular
mechanisms of HBV- and NAFLD-related HCC respectively, specifically the immune responses in liver,
along with current immunotherapy options.

DIRECT PRO-ONCOGENIC MECHANISMS

HBV
Genomic features are significantly different in the group of HBV-HCC compared with non-infected patients.
These results suggest that HBV-related HCC use alternative mechanisms for tumorigenesis to some extent.
A high frequency of p53 inactivation and stem cell genes overexpression provide a potential pathogenic
link between impaired cell reprogramming and HBV infection. Notably, these observations have clinical
implication since TP53 mutations were associated with poor prognosis only in HBV-related tumors.

Virally oncogenic proteins
HBV genome contains four overlapping open reading frames, including preS1/preS2/S, preCore/Core,
X and Pol, encoding viral proteins. Among them, hepatitis B X protein (HBx) is the most important
oncogenic protein. Mutated or deleted HBx is frequently detected in HCC and plays critical role in liver
carcinogenesis [14-16] . Although it is still debated, a growing body of evidence suggests that both wild type HBx
and truncated HBx promote tumorigenesis by abrogating cell-cycle arrest and apoptosis inhibition [17-19] . HBx
promotes HCC progression mainly through interaction with host factors including proteins and non-coding
RNAs. HBx mutants interact with Bcl-2 and farnesoid X receptor leading to enhanced carcinogenesis [20-22] .
HBx-cortactin (CTTN) interaction promotes HCC progression by up-regulating expression of CREB1
[23]
and its downstream targets, cyclin D1 and MMP9 . As a major conserved cellular pathway that controls
critical cell processes, the ubiquitin proteasome system is often hijacked by HBx, leading to dysregulated
ubiquitination. HBx stabilizes critical transcriptional oncoproteins Myc and PAX8 via blocking Skp2-
mediated ubiquitination [24,25] . Silencing lncRNA-MALAT1/miR-124 axis or miR-5188-FOXO1/β-catenin-
c-Jun feedback loop significantly block HBx-mediated upregulating stemness markers and reprogramming