Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression

Abstract Hepatitis B virus (HBV) integration, the HBx protein (and its mutants), and covalently closed circular DNA (cccDNA) are critical for HBV replication, packaging, and transmission to new host cells. Although nucleos(t)ide analogs (NAs) are a class of antiviral drugs that effectively suppress...

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Main Authors: Yang-Hsiang Lin, Ming-Wei Lai, Chau-Ting Yeh, Wey-Ran Lin
Format: Article
Language:English
Published: BMC 2025-06-01
Series:Cancer Cell International
Subjects:
Online Access:https://doi.org/10.1186/s12935-025-03849-0
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author Yang-Hsiang Lin
Ming-Wei Lai
Chau-Ting Yeh
Wey-Ran Lin
author_facet Yang-Hsiang Lin
Ming-Wei Lai
Chau-Ting Yeh
Wey-Ran Lin
author_sort Yang-Hsiang Lin
collection DOAJ
description Abstract Hepatitis B virus (HBV) integration, the HBx protein (and its mutants), and covalently closed circular DNA (cccDNA) are critical for HBV replication, packaging, and transmission to new host cells. Although nucleos(t)ide analogs (NAs) are a class of antiviral drugs that effectively suppress HBV replication, they do not eliminate cccDNA. This persistent cccDNA, often referred to as an “invisible bullet”, plays a pivotal role not only in the horizontal transmission of HBV but also within the context of hepatocellular carcinoma (HCC). Growing evidence reveals that noncoding RNAs (ncRNAs) are deeply involved in cancer progression, as well as the HBV life cycle and related pathogenesis, including liver inflammation, fibrosis, and HCC. This involvement occurs through various mechanisms, as ncRNAs regulate gene transcription, act as miRNA sponges, modulate signaling pathways, and influence downstream effects. These functions depend on the proper formation of RNA structures, which are critical for maintaining the biological activity of ncRNAs. The structure of RNAs appears to play a pivotal role in their functional capacity. Moreover, both ncRNAs and viral nucleotides contribute to G-quadruplex structure formation, which is essential for the HBV life cycle and cancer progression. In this review, we provide an updated overview of the mechanisms by which key ncRNAs mediate HBV/cccDNA actions in HCC progression and focus on their roles in gene expression and structural formation/modification.
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spelling doaj-art-85ebaafc27aa4d1f81ed59f023c404382025-08-20T02:10:35ZengBMCCancer Cell International1475-28672025-06-0125111310.1186/s12935-025-03849-0Perspectives on NcRNAs in HBV/cccDNA-driven HCC progressionYang-Hsiang Lin0Ming-Wei Lai1Chau-Ting Yeh2Wey-Ran Lin3Liver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalLiver Research Center, Chang Gung Memorial HospitalAbstract Hepatitis B virus (HBV) integration, the HBx protein (and its mutants), and covalently closed circular DNA (cccDNA) are critical for HBV replication, packaging, and transmission to new host cells. Although nucleos(t)ide analogs (NAs) are a class of antiviral drugs that effectively suppress HBV replication, they do not eliminate cccDNA. This persistent cccDNA, often referred to as an “invisible bullet”, plays a pivotal role not only in the horizontal transmission of HBV but also within the context of hepatocellular carcinoma (HCC). Growing evidence reveals that noncoding RNAs (ncRNAs) are deeply involved in cancer progression, as well as the HBV life cycle and related pathogenesis, including liver inflammation, fibrosis, and HCC. This involvement occurs through various mechanisms, as ncRNAs regulate gene transcription, act as miRNA sponges, modulate signaling pathways, and influence downstream effects. These functions depend on the proper formation of RNA structures, which are critical for maintaining the biological activity of ncRNAs. The structure of RNAs appears to play a pivotal role in their functional capacity. Moreover, both ncRNAs and viral nucleotides contribute to G-quadruplex structure formation, which is essential for the HBV life cycle and cancer progression. In this review, we provide an updated overview of the mechanisms by which key ncRNAs mediate HBV/cccDNA actions in HCC progression and focus on their roles in gene expression and structural formation/modification.https://doi.org/10.1186/s12935-025-03849-0HBVHBxCccDNANucleos(t)ide analogueHCCNcRNAs
spellingShingle Yang-Hsiang Lin
Ming-Wei Lai
Chau-Ting Yeh
Wey-Ran Lin
Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression
Cancer Cell International
HBV
HBx
CccDNA
Nucleos(t)ide analogue
HCC
NcRNAs
title Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression
title_full Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression
title_fullStr Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression
title_full_unstemmed Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression
title_short Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression
title_sort perspectives on ncrnas in hbv cccdna driven hcc progression
topic HBV
HBx
CccDNA
Nucleos(t)ide analogue
HCC
NcRNAs
url https://doi.org/10.1186/s12935-025-03849-0
work_keys_str_mv AT yanghsianglin perspectivesonncrnasinhbvcccdnadrivenhccprogression
AT mingweilai perspectivesonncrnasinhbvcccdnadrivenhccprogression
AT chautingyeh perspectivesonncrnasinhbvcccdnadrivenhccprogression
AT weyranlin perspectivesonncrnasinhbvcccdnadrivenhccprogression