Division of General Internal Medicine, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Kaohsiung Veterans General Hospital, Kaohsiung, Taiwan.
Aging (Albany NY). 2022 Jul 12;14(14):5710-5726. doi: 10.18632/aging.204170.
Direct-acting antivirals (DAAs) have achieved a sustained virological response (SVR) rate of 95-99% in treating HCV. Several studies suggested that treatment with sofosbuvir (SOF), one type of DAAs, may be associated with increased risk of developing HCC. The aim of this study is to investigate the potential mechanisms of SOF on the development of HCC. OR-6 (harboring full-length genotype 1b HCV) and Huh 7.5.1 cells were used to examine the effects of SOF on cell proliferation and migration of HCC cells. SOF-upregulated genes in OR-6 cells were inspected using next generation sequencing (NGS)and the clinical significance of these candidate genes was analyzed using The Cancer Genome Atlas (TCGA) database. We found that SOF increased cell proliferation and cell migration in OR-6 and Huh 7.5.1 cells. Several SOF-upregulated genes screened from NGS were confirmed by real-time PCR in OR-6 cells. Among these genes, PHOSPHO2, KLHL23, TRIM39, TSNAX-DISC1 and RPP21 expression were significantly elevated in the tumor tissues compared with the non-tumor tissues of HCC according to TCGA database. High expression of PHOSPHO2 and RPP21 was associated with poor overall survival of HCC patients. Moreover, knockdown of PHOSPHO2-KLHL23, TSNAX-DISC1, TRIM39 and RPP21 diminished cell proliferation and migration increased by SOF in OR-6 and Huh 7.5.1 cells. In conclusion, SOF-upregulated genes promoted HCC cell proliferation and migration, which might be associated with the development of HCC.
直接作用抗病毒药物 (DAAs) 在治疗 HCV 方面实现了 95-99%的持续病毒学应答 (SVR) 率。几项研究表明，使用 DAA 中的索非布韦 (SOF) 治疗可能与 HCC 发生风险增加相关。本研究旨在探讨 SOF 促进 HCC 发展的潜在机制。OR-6（携带全长基因型 1b HCV）和 Huh 7.5.1 细胞用于研究 SOF 对 HCC 细胞增殖和迁移的影响。使用下一代测序 (NGS) 检查 SOF 在 OR-6 细胞中上调的基因，并使用癌症基因组图谱 (TCGA) 数据库分析这些候选基因的临床意义。我们发现 SOF 增加了 OR-6 和 Huh 7.5.1 细胞的增殖和迁移。从 NGS 筛选出的几个 SOF 上调基因在 OR-6 细胞中通过实时 PCR 得到了验证。在这些基因中，根据 TCGA 数据库，PHOSPHO2、KLHL23、TRIM39、TSNAX-DISC1 和 RPP21 的表达在 HCC 的肿瘤组织中明显高于非肿瘤组织。PHOSPHO2 和 RPP21 的高表达与 HCC 患者的总生存不良相关。此外，PHOSPHO2-KLHL23、TSNAX-DISC1、TRIM39 和 RPP21 的敲低减弱了 SOF 对 OR-6 和 Huh 7.5.1 细胞增殖和迁移的促进作用。总之，SOF 上调的基因促进了 HCC 细胞的增殖和迁移，这可能与 HCC 的发生有关。
