Lin Yang-Hsiang, Lai Ming-Wei, Yeh Chau-Ting, Lin Wey-Ran
Liver Research Center, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan, Taiwan.
Cancer Cell Int. 2025 Jun 21;25(1):224. doi: 10.1186/s12935-025-03849-0.
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.
乙型肝炎病毒（HBV）整合、HBx蛋白（及其突变体）和共价闭合环状DNA（cccDNA）对于HBV复制、包装以及向新宿主细胞的传播至关重要。尽管核苷（酸）类似物（NAs）是一类能有效抑制HBV复制的抗病毒药物，但它们并不能消除cccDNA。这种持续存在的cccDNA，常被称为“隐形子弹”，不仅在HBV的水平传播中起关键作用，而且在肝细胞癌（HCC）的背景下也发挥着重要作用。越来越多的证据表明，非编码RNA（ncRNAs）深度参与癌症进展以及HBV生命周期和相关发病机制，包括肝脏炎症、纤维化和HCC。这种参与通过多种机制发生，因为ncRNAs调节基因转录、充当miRNA海绵、调节信号通路并影响下游效应。这些功能取决于RNA结构的正确形成，而RNA结构对于维持ncRNAs的生物学活性至关重要。RNA的结构似乎在其功能能力中起关键作用。此外，ncRNAs和病毒核苷酸都有助于G-四链体结构的形成，这对于HBV生命周期和癌症进展至关重要。在本综述中，我们提供了关键ncRNAs在HCC进展中介导HBV/cccDNA作用机制的最新概述，并重点关注它们在基因表达和结构形成/修饰中的作用。
