Université de Strasbourg, Inserm, Institut de Recherche sur Les Maladies Virales et Hépatiques UMR_S1110, Strasbourg, France.
Institut Hospitalo-Universitaire, Pôle Hépato-digestif, Nouvel Hôpital Civil, Strasbourg, France.
Life Sci Alliance. 2021 Jul 21;4(9). doi: 10.26508/lsa.202101036. Print 2021 Sep.
Chronic hepatitis B virus (HBV) infection is a major cause of hepatocellular carcinoma (HCC) world-wide. The molecular mechanisms of viral hepatocarcinogenesis are still partially understood. Here, we applied two complementary single-cell RNA-sequencing protocols to investigate HBV-HCC host cell interactions at the single cell level of patient-derived HCC. Computational analyses revealed a marked HCC heterogeneity with a robust and significant correlation between HBV reads and cancer cell differentiation. Viral reads significantly correlated with the expression of HBV-dependency factors such as in different tumor compartments. Analyses of virus-induced host responses identified previously undiscovered pathways mediating viral carcinogenesis, such as E2F- and MYC targets as well as adipogenesis. Mapping of fused HBV-host cell transcripts allowed the characterization of integration sites in individual cancer cells. Collectively, single-cell RNA-Seq unravels heterogeneity and compartmentalization of both, virus and cancer identifying new candidate pathways for viral hepatocarcinogenesis. The perturbation of pro-carcinogenic gene expression even at low HBV levels highlights the need of HBV cure to eliminate HCC risk.
慢性乙型肝炎病毒（HBV）感染是全球肝细胞癌（HCC）的主要病因。病毒致癌的分子机制仍部分未知。在此，我们应用两种互补的单细胞 RNA 测序方案，在患者来源的 HCC 的单细胞水平上研究 HBV-HCC 宿主细胞相互作用。计算分析显示 HCC 具有明显的异质性，HBV 读数与肿瘤细胞分化之间存在强大而显著的相关性。病毒读数与 HBV 依赖性因子的表达显著相关，如不同肿瘤区室中的 。对病毒诱导的宿主反应的分析确定了以前未发现的介导病毒致癌的途径，如 E2F 和 MYC 靶标以及脂肪生成。融合的 HBV-宿主细胞转录本的映射允许在单个癌细胞中表征整合位点。总之，单细胞 RNA-Seq 揭示了病毒和癌症的异质性和区室化，确定了病毒性肝细胞癌发生的新候选途径。即使在低 HBV 水平下，促癌基因表达的扰动也强调了需要 HBV 治愈以消除 HCC 风险。
