Indian Institute of Science, Bangalore, India.
Institute of Post Graduate Medical Education & Research, Kolkata, India.
J Gen Virol. 2022 Dec;103(12). doi: 10.1099/jgv.0.001809.
Chronic hepatitis C virus (HCV) infection is a leading cause of end-stage liver diseases, such as fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Several cellular entities, including paraspeckles and their related components, are involved in viral pathogenesis and cancer progression. NEAT1 lncRNA is a major component of paraspeckles that has been linked to several malignancies. In this study, analysis of the Cancer Genome Atlas (TCGA) database and validation in HCV-induced HCC tissue and serum samples showed significantly high expression of NEAT1 in patients with liver cancer. Moreover, we found that NEAT1 levels increased upon HCV infection. To further understand the mechanism of NEAT1-induced HCC progression, we selected one of its targets, miR-9-5 p, which regulates BGH3 mRNA levels. Interestingly, miR-9-5 p levels were downregulated upon HCV infection, whereas BGH3 levels were upregulated. Additionally, partial NEAT1 knockdown increased miR-9-5 p levels and decreased BGH3 levels, corroborating our initial results. BGH3 levels were also upregulated in HCV-induced HCC and TCGA tissue samples, which could be directly correlated with NEAT1 levels. As a known oncogene, BGH3 is directly linked to HCC progression mediated by NEAT1. We also found that NEAT1 levels remained upregulated in serum samples from patients treated with direct-acting antivirals (DAA), indicating that NEAT1 might be a molecular trigger that promotes HCC development. Collectively, these findings provide molecular insights into HCV-induced HCC progression via the NEAT1-miR-9-BGH3 axis.
慢性丙型肝炎病毒（HCV）感染是肝纤维化、肝硬化和肝细胞癌（HCC）等终末期肝病的主要原因。包括核仁小体及其相关成分在内的几种细胞实体参与病毒发病机制和癌症进展。NEAT1 lncRNA 是核仁小体的主要组成部分，与多种恶性肿瘤有关。在这项研究中，对癌症基因组图谱（TCGA）数据库的分析和 HCV 诱导的 HCC 组织和血清样本的验证表明，肝癌患者的 NEAT1 表达明显升高。此外，我们发现 HCV 感染后 NEAT1 水平增加。为了进一步了解 NEAT1 诱导 HCC 进展的机制，我们选择了其靶标之一 miR-9-5p，它调节 BGH3 mRNA 水平。有趣的是，miR-9-5p 水平在 HCV 感染后下调，而 BGH3 水平上调。此外，部分 NEAT1 敲低增加了 miR-9-5p 水平并降低了 BGH3 水平，与我们的初步结果一致。在 HCV 诱导的 HCC 和 TCGA 组织样本中，BGH3 水平也上调，这与 NEAT1 水平直接相关。作为已知的癌基因，BGH3 与 NEAT1 介导的 HCC 进展直接相关。我们还发现，直接作用抗病毒药物（DAA）治疗的患者血清样本中 NEAT1 水平仍然升高，表明 NEAT1 可能是促进 HCC 发展的分子触发因素。综上所述，这些发现提供了 HCV 诱导的 HCC 进展通过 NEAT1-miR-9-BGH3 轴的分子见解。
