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Ding et al. Hepatoma Res 2019;5:10 I http://dx.doi.org/10.20517/2394-5079.2018.115 Page 3 of 8

that HBV RNA itself contributes to the progression of HBV-associated diseases through direct and indirect
ways [14-23] . Nucleos(t)ide analogues (NAs) exerts its antiviral function through inhibiting the reverse
transcription of HBV. As cccDNA is unaffected and its transcriptional activity remains, the formation of
HBV RNAs continues. Therefore, in some CHB patients, although HBV DNA was maintained at extremely
low level by anti-HBV drugs, serious HBV-related complications still occurred.

HBV RNA and CHB
Persistent infection of HBV is the main cause of CHB, and continuous virus replication will eventually
results in the inflammation and fibrosis of liver, which is the key characteristic of CHB. The effect of HBV
RNA on HBV replication other than serving as reverse transcription template is poorly understood by now.
However, HBV RNA may facilitate viral replication through deregulating the functions of host microRNAs.
For example, one of the micro RNAs which is highly and specifically expressed in hepatocytes, miR-122,
inhibits the replication of HBV in the liver. It has been reported that HBV RNA could act as sponges to bind
and sequester endogenous miR-122, then the down-regulated expression or decreased function of miR-122
would increase level of cyclin G1, which further represses the expression of p53, leading to upregulation
of HBV transcription via blocking specific combination of p53 with HBV enhancer elements [14,16] . It also
has been reported that the miR-15 family might regulate HBV replication. The overexpression of the miR-
15 family members, miR-15a and miR-16-1, inhibits HBV replication. As HBV RNA can sequester these
miRNAs, cyclin D1, the target of miR-15a and miR-16-1, is up-regulation, which makes a significant
[17]
contribution HBV replication . Furthermore, the viral-derived miRNA, miR-3, suppressed the transcription
[18]
[18]
of pgRNA and HBc protein translation by targeting the 3.5-kb transcript of HBV . Yang et al. thought
that the inhibition of HBV replication might contribute to the development of persistent infection in CHB
patients. However, more and further studies are need to verify his hypothesis.

HBV RNA and hepatic fibrosis
The cycle of continuous inflammation caused by viral replication and self-repairing of hepatocytes leads to
the accumulation of extracellular matrix proteins, and eventually results in the development of fibrosis. The
transforming growth factor-β (TGF-β) pathway and nuclear factor-κB pathway together play an important
role in the process of liver fibrosis. As mentioned above, miR-122 is down-regulated through sequestration
[14]
caused by the role of HBV RNA as miRNA sponge in HBV-infected liver . The altered expression of
miR-122 activates the synthesis of collagen via the TGF-β pathway, which participates in the liver fibrosis
[19]
[20]
process . Furthermore, the study of Sato et al. indicated that the inflammatory factors induced by the 5’-ε
region of HBV pgRNA may aggravate the degree of inflammation and exacerbate the fibrosis of liver.
HBV RNA and hepatocellular carcinoma
Although the direct relationship between HBV RNA and the occurrence of hepatocellular carcinoma (HCC)
[6]
has not been reported so far, the study of Wang et al. showed that serum HBVRNA level correlates with
the intrahepatic HBVRNA level, and serum HBVRNA level reflects the severity of histological changes
and is associated with liver disease progression during NAs therapy, even in the CHB patients whose viral
replication is suppressed. This means that serum HBV RNA is associated with the degree of intrahepatic
inflammation and may be used as a new biomarker for reflecting hepatocarcinogenesis, especially in the
CHB patients whose serum HBV DNA is suppressed by NAs therapy. It has also been reported that the 5’-ε
region of HBV pgRNA induces the production of interferons and inflammatory cytokines in hepatocytes,
[20]
which may lead to histological changes and the aggravation of fibrosis . As we all know, the cirrhosis
caused by liver fibrosis is a precancerous lesion of HCC.

These results together show that HBV RNA itself might promote the occurrence of HCC, at least to some
[7]
extent. Moreover, the study of Halgand et al. showed that HBV pgRNA is detectable more frequently in
HCC non-tumor tissues (90%) than in HCC tumor tissues (67%). When detectable in both compartments,
the level of pgRNA was higher in non-tumor tissues than in tumor tissues. And the detection of pgRNA in