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Page 2 of 9 Yoon. Hepatoma Res 2018;4:42 I http://dx.doi.org/10.20517/2394-5079.2018.23

In an era of precision medicine for cancer treatment, it is essential to investigate the molecular mechanisms
of carcinogenesis and tumor progression. In addition to array-based comparative analyses, genome-wide
association studies (GWAS), next-generation sequencing (NGS), and RNA sequencing analyses for cancer
research, studies on host immune mechanisms associated with immune evasion of cancer are also required
to develop tumor immunotherapy.

It is generally accepted that hepatocarcinogenesis is very complex and occurs through a multistep biological
process during malignant transformation of normal hepatocytes in which various factors, including genetic
and epigenetic alterations, are involved. Specifically, recent advances in NGS technologies have facilitated
a more profound understanding of the molecular mechanisms of HCC, which have contributed to the de-
velopment of targeted therapies for cancers by identifying genes and associated signaling involved in carci-
nogenesis and tumor progression. Despite these advances, it remains difficult to effectively treat advanced
HCC because most advanced cases are accompanied by poor liver function and liver cirrhosis. Surgical ap-
proaches, including resection and liver transplantation, are not available in these cases, so molecular targeted
therapy combined with immunotherapy has become an alternative strategy to prolong patients’ survival. To
this end, further investigation of the molecular pathways involved in hepatocarcinogenesis and tumor pro-
gression is indispensable.

In this article, I discuss recent advances in molecular pathogenesis based on major etiologicfactors for the
development of HCC.

MOLECULAR MECHANISMS OF HBV-RELATED HCC
Among the major risk factors for HCC, HBV is the most common causative agent that increases the inci-
dence of HCC in East Asia and sub-Saharan Africa. The HBV genome contains four genes (C, S, X and P),
which encode the core protein, envelope protein, X protein and a polymerase. Among them, hepatitis B X
protein (HBx) is known to have a critical role in the development of HCC. Accumulating evidence reveals
[5]
that HBx has multifunctional activities including interruption of apoptosis in hepatocytes and DNA re-
[6]
pair mechanisms through transcriptional regulations of p53 , facilitation of cellular signal transduction,
cell cycle progression, and maintenance of genetic stability of HBx through interactions with different host
[7]
factors .
Chronic HBV infection enables viral DNA to integrate into the host genome, leading to an oncogenic trans-
formation. A recent NGS study revealed that HBV integration was found in more than 80% of HBV positive
[8]
HCC and was more extensive in tumor tissue compared with surrounding non-tumor tissue . In particular,
three cancer-associated genes, telomerase reverse transcriptase (TERT), mixed-lineage leukemia 4 (MLL4)
and cyclin E1 (CCNE1) were observed at frequent integration sites in HBV positive tumors. These findings
suggest a significant association between HBV integration and hepatocarcinogenesis. Moreover, mutations
[9]
in TERT promoter are found in more than 50% of HCC tissue . Although the mechanism by which TERT
is activated in cancer is not clearly understood, and a recent study revealed that the GA-binding protein
transcription factor (GABP), a member of the E-twenty six (ETS) transcription factor family, is selectively
[10]
recruited to the mutated TERT promoter and activates TERT expression .

Accumulating evidence has shown that HBx plays important roles in hepatocarcinogenesis. Several mecha-
nisms by which HBx may function at the molecular and cellular levels are as follows: (1) transactivation of
promoters of cAMP response element binding protein (CREB) response element (CRE)-containing genes,
[11]
including the oncogene Yes-associated protein (YAP) ; (2) alteration of the DNA specificity of CREB and
[12]
activating transcription factor 2 (ATF-2), resulting in binding and activation of the HBV enhancer ; (3)
modulation of the DNA binding specificity of the p53 tumor suppressor, resulting in altered expression of