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Page 4 of 9 Zhang et al. Hepatoma Res 2019;5:14 I http://dx.doi.org/10.20517/2394-5079.2018.117

decades ago, other ncRNAs including lncRNAs, snoRNAs, siRNAs and piRNAs have been surfaced and
[42]
proved to be essential players in cancer pathogenesis . Therefore, the combination of lncRNAs with other
ncRNAs should not be underestimated in the onset and progression of HCC.

Epigenetic markers
DNA methylation affects the phenotype mainly through expression of the corresponding genes, methylation
profiles could reflect the biological characteristics of HCC if “passive methylation” could be eliminated
appropriately. A number of results have shown the predictive value of selected methylation events on
[43]
survival . After hepatectomy, the methylation map of liver may reflect the recurrence-free survival of HCC
[44]
patients . It has been reported that the determination of DNA methylation as a potential tumor marker
[45]
is able to monitor the circulating tumor DNA in plasma samples . High levels of trimethylated histone
H3 lysine 4 (H3K4me3) were usually accompanied by the decreased overall survival and poor prognosis
[46]
in HCC . Another research also indicated that high levels of H3K27me3 forecasted poor prognosis and
aggressive tumor characteristics, such as large tumor size, vascular invasion, multiplicity of tumors and poor
[47]
differentiation . To better understand the roles in HCC, more studies using accurate detection methods,
such as ChIP-sequencing, may be developed to evaluate these specific DNA-protein modifications.

About the traditional biomarkers, because the false negative rate of alpha-fetoprotein (AFP) is about 40% for
early-stage HCC patients, 15%-30% of all the patients, even patients with advanced HCC, AFP levels remain
[48]
normal . Lens culinaris agglutinin (LCA)-reactive AFP (AFP-L3) as an isoform of AFP may improve the
[49]
detective rate for small lesion of liver cancer . It has been reported that C-carboxy prothrombin (DCP)
has a higher specificity for HCC than AFP but is less sensitive. Thus, the combination of AFP, AFP-L3, and
[50]
DCP seems to significantly improve HCC diagnostic accuracy . The combination of Glypican-3 (GPC3) as
[51]
a novel tumor marker of HCC with AFP proves the sensitivity but not the specificity in HCC diagnosis .
Moreover, the combination of the NH2-terminal portion of GPC3 which is also called soluble GPC3 with
[52]
AFP can improve overall sensitivity from 50% to 72% . Interestingly, the dynamic changes of plasma
Hsp90α in liver cancer patients can detect the condition of treatment, such as surgery and interventional
[53]
therapy . Serum Dickkopf WNT signaling pathway inhibitor 1 (DKK1) was reported to be a useful
[54]
biomarker for diagnosis of HCC by a large-scale and multicenter study . Paraoxonase 1 (PON1) has been
proposed as a circulating protein biomarker since high serum levels in HCC patients concomitantly infected
[55]
with HCV infection has been observed . PON1-fucosylated level protein has been helpful in distinguishing
[56]
early HCC from liver cirrhosis patients even with low AFP levels .

THERAPY FOR HCC
Prevention and management of HBV infection
Based on hepatocarcinogenesis, prevention of HBV infection is a key step to reduce the incidence of liver
cancer. There is a renewed interest regarding the understanding of various steps of the HBV replication
cycle, as well as specific virus-host cell interactions, to define new targets and develop new antiviral
drugs. Basically, the HBV covalently closed circular DNA (HBV cccDNA) is pivotal for persistent HBV
infection and recurrence by the end of treatment. As far as we know, the cccDNA usually organizes into
a minichromosome with histone 3 and H4 proteins and other nonhistone proteins, such as HBx, HBV
[57]
core protein, and host transcription factors . Even though recent therapies can successfully control the
viral replication, but they fail to eliminate cccDNA completely. Demonstrating the molecular mechanisms
and screening critical factors involved in cccDNA may make it come true to develop more precisely
[58]
targeted therapeutic strategies and cure HBV-related HCC patients . It covers a series of inhibition of
viral replication processes such as entry inhibitors, capsid assembly modulators, approaches aiming at the
secretion of viral envelope proteins, drugs targeting HBV cccDNA, and siRNAs targeting viral transcripts.
Restoration of immune responses is a complementary approach. HBV chronic infection and high viral
load have been associated with higher levels of soluble programmed cell death protein 1, and this results