Joint Laboratory for Translational Cancer Research of Chinese Medicine of the Ministry of Education of the People's Republic of China, Guangdong-Hong Kong-Macau Joint Laboratory on Chinese Medicine and Immune Disease Research, International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, China.
Guangxi Key Laboratory of Bioactive Molecules Research and Evaluation, College of Pharmacy, Guangxi Medical University, Nanning, China.
Viral Immunol. 2023 Apr;36(3):209-221. doi: 10.1089/vim.2022.0130. Epub 2023 Mar 21.
Pegylated interferon alfa-2b (Peg-IFN -2b), a first-line treatment for hepatitis B virus (HBV) infection, can significantly achieve HBsAg clearance in clinic. However, only 30-40% of patients had achieved HBsAg clearance after Peg-IFN -2b administration. The biological targets and the underline mechanisms that distinguish sensitive and insensitive populations to interferon therapy are still unclear. In the present study, only 33.33% of patients achieved HBsAg loss after 48 weeks of Peg-IFN -2b therapy. Thirty-six exosomal-microRNAs (miRNAs) in the sensitive group were identified that might induce sensitivity specifically, whereas 32 exosomal-miRNAs in the insensitive group were identified that might induce insensitive specifically. Among these miRNAs, five miRNAs (miR-425-5p, miR-8485, miR-619-5p, miR-181a-5p, and miR-484) might increase the sensitivity to Peg-IFN -2b therapy by regulating key genes GSK3B, KRAS, FLT1, or GRB2, whereas, 13 miRNAs (miR-195-5p, miR-215-5p, miR-9-5p, miR-130a-3p, miR-214-3p, miR-149-5p, miR-429, miR-200b-3p, miR-200c-3p, miR-16-2-3p, miR-141-3p, miR-200a-3p, and miR-218-5p) might decrease the sensitivity to Peg-IFN -2b therapy by regulating key genes, FGF2, GSK3B, PDGFRA, FGFR1, KRAS, FLT1, MYC, TGFB2, EFNA1, MAPK9, or GRB2. Furthermore, seven novel miRNAs, namely Novel_352, Novel_459, Novel_527, Novel_677, Novel_717, Novel_749, and Novel_801 were found to be downregulated specifically in the sensitive group, whereas, Novel_142 and Novel_664 were found to be downregulated specifically in the insensitive group. Our data indicate that the serum exosomal-miRNAs could be involved in regulating the sensitivity of chronic HBV (CHB) patients to Peg-IFN -2b therapy, which might suggest potential novel therapeutic biomarkers and standard options for CHB patients. Clinical Trials.gov ID: NCT04035837.
聚乙二醇干扰素 alfa-2b（Peg-IFN-2b）是乙型肝炎病毒（HBV）感染的一线治疗药物，可显著实现 HBsAg 清除。然而，只有 30-40%的患者在 Peg-IFN-2b 治疗后实现了 HBsAg 清除。区分干扰素治疗敏感和不敏感人群的生物学靶点和潜在机制仍不清楚。在本研究中，只有 33.33%的患者在 Peg-IFN-2b 治疗 48 周后失去了 HBsAg。在敏感组中鉴定出 36 种外泌体 microRNAs（miRNAs），这些 miRNA 可能特异性诱导敏感性，而在不敏感组中鉴定出 32 种外泌体 miRNAs，这些 miRNAs 可能特异性诱导不敏感性。在这些 miRNA 中，miR-425-5p、miR-8485、miR-619-5p、miR-181a-5p 和 miR-484 可能通过调节 GSK3B、KRAS、FLT1 或 GRB2 等关键基因来增加对 Peg-IFN-2b 治疗的敏感性，而 miR-195-5p、miR-215-5p、miR-9-5p、miR-130a-3p、miR-214-3p、miR-149-5p、miR-429、miR-200b-3p、miR-200c-3p、miR-16-2-3p、miR-141-3p、miR-200a-3p 和 miR-218-5p 通过调节关键基因 FGF2、GSK3B、PDGFRA、FGFR1、KRAS、FLT1、MYC、TGFB2、EFNA1、MAPK9 或 GRB2 降低对 Peg-IFN-2b 治疗的敏感性。此外，还发现了七个新的 miRNA，即 Novel_352、Novel_459、Novel_527、Novel_677、Novel_717、Novel_749 和 Novel_801，它们在敏感组中特异性下调，而 Novel_142 和 Novel_664 在不敏感组中特异性下调。我们的数据表明，血清外泌体 miRNAs 可能参与调节慢性乙型肝炎（CHB）患者对 Peg-IFN-2b 治疗的敏感性，这可能为 CHB 患者提供潜在的新的治疗生物标志物和标准选择。临床试验注册号：NCT04035837。
