遗传因素在 HCV 基因 1b 型感染肝硬化患者的 NS5A 关键区域与肝细胞癌相关。

Genetic Determinants in a Critical Domain of NS5A Correlate with Hepatocellular Carcinoma in Cirrhotic Patients Infected with HCV Genotype 1b.

机构信息

Department of Experimental Medicine, University of Rome "Tor Vergata", 00133 Rome, Italy.

Department of Clinical and Experimental Medicine, University of Sassari, 07100 Sassari, Italy.

出版信息

Viruses. 2021 Apr 23;13(5):743. doi: 10.3390/v13050743.

DOI:10.3390/v13050743

PMID:33922732

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8146897/

Abstract

HCV is an important cause of hepatocellular carcinoma (HCC). HCV NS5A domain-1 interacts with cellular proteins inducing pro-oncogenic pathways. Thus, we explore genetic variations in NS5A domain-1 and their association with HCC, by analyzing 188 NS5A sequences from HCV genotype-1b infected DAA-naïve cirrhotic patients: 34 with HCC and 154 without HCC. Specific NS5A mutations significantly correlate with HCC: S3T (8.8% vs. 1.3%, = 0.01), T122M (8.8% vs. 0.0%, < 0.001), M133I (20.6% vs. 3.9%, < 0.001), and Q181E (11.8% vs. 0.6%, < 0.001). By multivariable analysis, the presence of >1 of them independently correlates with HCC (OR (95%CI): 21.8 (5.7-82.3); < 0.001). Focusing on HCC-group, the presence of these mutations correlates with higher viremia (median (IQR): 5.7 (5.4-6.2) log IU/mL vs. 5.3 (4.4-5.6) log IU/mL, = 0.02) and lower ALT (35 (30-71) vs. 83 (48-108) U/L, = 0.004), suggesting a role in enhancing viral fitness without affecting necroinflammation. Notably, these mutations reside in NS5A regions known to interact with cellular proteins crucial for cell-cycle regulation (p53, p85-PIK3, and β-catenin), and introduce additional phosphorylation sites, a phenomenon known to ameliorate NS5A interaction with cellular proteins. Overall, these results provide a focus for further investigations on molecular bases of HCV-mediated oncogenesis. The role of theseNS5A domain-1 mutations in triggering pro-oncogenic stimuli that can persist also despite achievement of sustained virological response deserves further investigation.

摘要

丙型肝炎病毒（HCV）是肝细胞癌（HCC）的重要病因。HCV NS5A 结构域 1 与细胞蛋白相互作用，诱导致癌途径。因此，我们通过分析 188 例 HCV 基因型 1b 感染、DAA 初治肝硬化患者的 NS5A 序列，研究 NS5A 结构域 1 的遗传变异及其与 HCC 的相关性：34 例 HCC 患者，154 例非 HCC 患者。特定的 NS5A 突变与 HCC 显著相关：S3T（8.8%比 1.3%， = 0.01）、T122M（8.8%比 0.0%， < 0.001）、M133I（20.6%比 3.9%， < 0.001）和 Q181E（11.8%比 0.6%， < 0.001）。多变量分析显示，存在≥1 种这些突变与 HCC 独立相关（OR（95%CI）：21.8（5.7-82.3）； < 0.001）。在 HCC 组中，这些突变的存在与较高的病毒血症相关（中位数（IQR）：5.7（5.4-6.2）log IU/mL 比 5.3（4.4-5.6）log IU/mL， = 0.02）和较低的 ALT（35（30-71）比 83（48-108）U/L， = 0.004），提示其在增强病毒适应性而不影响坏死性炎症方面起作用。值得注意的是，这些突变位于 NS5A 区域，已知该区域与细胞周期调节相关的关键细胞蛋白（p53、p85-PIK3 和 β-连环蛋白）相互作用，并引入额外的磷酸化位点，这一现象已知可改善 NS5A 与细胞蛋白的相互作用。总之，这些结果为进一步研究 HCV 介导的致癌作用的分子基础提供了重点。这些 NS5A 结构域 1 突变在触发致癌刺激方面的作用，即使在持续病毒学应答（SVR）实现后仍能持续，值得进一步研究。