Page 26 - JCTR-11-4

Journal of Clinical and
Translational Research Propranolol as a treatment for HCC

continue after the intake of nucleoside analogs. Upon xenograft model reduced VEGFA levels and tumor growth,
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entry into the nucleus of the partially double-stranded identifying the IGF2BP3-VEGFA axis as a potential
circular DNA, single-stranded DNA gaps are closed, and therapeutic target for antiangiogenic therapy in HBV-
the HBV genome is transformed into a covalently closed related HCC. 15
circular, double-stranded DNA (cccDNA). cccDNA serves Another major oncogenic mechanism involves HBV
as a template for viral mRNA transcription and synthesis integration into the host genome, which subsequently
rather than replication. HBV genome is small and contains disrupts essential cellular regulatory functions required for
four overlapping ORFs encoding HBx protein, envelope cell survival and proliferation. Interacting with different
(S antigen), reverse transcriptase/polymerase (Pol), and cellular proteins and regulating their functions, the HBV
capsid (core). Pre-genomic RNA (pgRNA), the largest X protein (HBx) is a key molecule in promoting the
HBV transcript, is a terminally redundant viral replication development of HCC. HBx can activate multiple signaling
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intermediate. The viral reverse-transcriptase/polymerase pathways involved in cell proliferation and survival, such
of the infected hepatocyte cytoplasm replicates by as the PI3K/Akt and MAPK/ERK pathways. HBx can
reversing the pgRNA to the DNA genome. The HBsAg also disrupt DNA repair mechanisms, leading to genomic
proteins either secrete the replicating, encapsulated viral instability and mutation accumulation. Another essential
genome to the nucleus to enhance the nuclear reservoir mechanism is the induction of chronic inflammation
of cccDNA or sequester it as capsid buds within the by HBV infection, which creates a microenvironment
endoplasmic reticulum. The encapsulated virion is released conducive to the initiation and progression of tumors.
from the cell; numerous studies have demonstrated that During chronic inflammation, inflammatory cytokines
HBV release from cells is regulated by multivesicular stimulate cell proliferation, angiogenesis, and tissue
body components. Three stages may be distinguished in remodeling. By releasing pro-inflammatory mediators,
5
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the hepadnaviral genome replication process. First, the HBV-induced immune responses can also contribute to
icosahedral core of the infectious virions contains rcDNA, liver injury and promote the development of HCC. These
which is a circular, partly double-stranded DNA molecule pro-inflammatory mediators exacerbate the inflammatory
of around 3.2 kb. Second, within the host cell’s nucleus, response, thereby perpetuating liver injury and promoting
the rcDNA transforms into a plasmid-like cccDNA upon the development of HCC. In addition, HBV infection can
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infection. Finally, pgRNA, which is preferentially packed interfere directly with cellular processes involved in DNA
into progeny capsids and reverse-transcribed by the repair and replication, resulting in genomic instability and
co-packaged P protein into new rcDNA genomes, is one an increased risk of mutations. These mutations contribute
of the genomic and subgenomic RNAs produced by the to the progression of HCC. Furthermore, immune
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cccDNA. 12 responses elicited by HBV are also capable of recruiting
2.3. Mechanisms of HBV-induced HCC immune cells such as macrophages and lymphocytes,
which produce other pro-inflammatory cytokines that
Prevention of HBV infection and early detection of HCC lead to tissue damage and tumor development. This
are crucial for reducing the disease’s burden. Vaccination vicious cycle between chronic inflammation, immune
against HBV has proven to be highly effective at preventing response, genomic instability, and mutagenesis represents
new infections, and efforts should be made to increase the complexity of HBV-induced HCC formation. All these
global vaccination rates. Regular screening for HBV processes should be unveiled to develop targeted therapies
infection can assist in identifying individuals at risk for to prevent this complicated sequence and improve the
HCC, enabling early intervention and treatment. Public prognosis of HBV-related HCC patients. 17
13
health campaigns should emphasize the significance of
vaccination and screening, especially among high-risk 3. Molecular mechanisms of HCV in the
populations such as those with a family history of HBV or development of HCC
in areas with a high prevalence rate. In HBV-related HCC,
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angiogenesis is critically regulated by vascular endothelial 3.1. HCV
growth factor A (VEGFA), whose post-transcriptional HCV is a member of the Flaviviridae family of enveloped
control by HBV remains unclear. It has been revealed RNA viruses. The 9 kb long, positive-strand, single-
that HBV increases m6A methylation of VEGFA mRNA, stranded RNA genome of HCV, similar to other flaviviruses,
thereby upregulating the RNA-binding protein IGF2BP3, is translated as a polyprotein, which is processed by
stabilizing VEGFA in an m6A-dependent manner, and proteases into four functional proteins at the C-terminus.
enhancing endothelial cell migration and tube formation. They comprise non-structural proteins involved in the
Knockdown of IGF2BP3 in an HBV-associated HCC replication of the virus, two envelope glycoproteins (E1

Volume 11 Issue 4 (2025) 20 doi: 10.36922/JCTR025080010