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Volume 41 Issue 3
June 2026

    . doi: 10.1016/j.virs.2026.03.001
    Citation: Mengxian Lin, Kunqi Chen, Hang Li, Xinjian Lin, Shuxiang Wu, Xu Lin. Hepatitis B virus promotes hepatocellular carcinoma progression by disrupting NSUN2/YBX1-mediated m5C modification of PTEN mRNA .VIROLOGICA SINICA, 2026, 41(3) : 543-560.  http://dx.doi.org/10.1016/j.virs.2026.03.001
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    乙型肝炎病毒通过抑制NSUN2及YBX1介导的PTEN mRNA m5C修饰促进肝癌进展

    • a. 福建医科大学消化道恶性肿瘤教育部重点实验室;

    • b. 福建医科大学肿瘤微生物学福建省重点实验室

    • 乙型肝炎病毒（HBV）与肝细胞癌（HCC）的进展密切相关，部分机制与其对抑癌基因磷酸酶与张力蛋白同源物（PTEN）的调控有关。尽管HBV对PTEN的转录水平调控已较为明确，但其转录后调控机制仍知之甚少。鉴于RNA 5-甲基胞嘧啶（m5C）修饰可影响转录后基因调控并与肿瘤发生相关，本研究探讨HBV是否通过m5C修饰调控PTEN。甲基化RNA免疫沉淀（MeRIP）-定量聚合酶链式反应结果显示，在HBV产生细胞中，PTEN mRNA上的m5C水平显著降低。MeRIP测序进一步发现，在HBV产生的HepAD38/去四环素诱导细胞中，PTEN编码序列区（chr10:89717747–89717771）的m5C修饰下降，其中chr10:89717756为关键位点，HBV在该位点抑制m5C富集并伴随PTEN表达降低。机制研究表明，m5C“写入酶”NOP2/Sun RNA甲基转移酶2（NSUN2）与m5C“读取蛋白”Y-box结合蛋白1（YBX1）以m5C依赖方式稳定PTEN mRNA；HBV可干扰该通路，通过NSUN2和YBX1介导的m5C修饰削弱PTEN mRNA稳定性。过表达NSUN2或YBX1可减弱HBV诱导的增殖、迁移和侵袭，而PTEN抑制剂VO-Ohpic可部分逆转上述效应。小型乙肝表面抗原与乙肝X蛋白可下调NSUN2和YBX1，将病毒蛋白与PTEN抑制相关联。此外，HBV与HBV转基因（HBV-Tg）小鼠、HBV感染的原代人肝细胞以及HBV阳性HCC临床标本中NSUN2表达降低相关，支持该发现的生理与临床意义。综上，本研究揭示NSUN2/YBX1/PTEN轴可能成为HBV相关HCC的潜在治疗靶点。

    Hepatitis B virus promotes hepatocellular carcinoma progression by disrupting NSUN2/YBX1-mediated m5C modification of PTEN mRNA

    • a. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China;

    • b. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China

    • Hepatitis B virus (HBV) has been implicated in hepatocellular carcinoma (HCC) progression, partly through regulation of the tumor suppressor phosphatase and tensin homolog (PTEN). Although transcriptional regulation of PTEN by HBV is well characterized, its post-transcriptional regulation remains poorly understood. Because RNA 5-methylcytosine (m5C) modification influences post-transcriptional gene control and cancer development, we investigated whether HBV modulates PTEN through m5C. Methylated RNA immunoprecipitation (MeRIP)-quantitative polymerase chain reaction showed a marked reduction in m5C on PTEN mRNA in HBV-producing cells. MeRIP sequencing further identified decreased m5C within the PTEN coding sequence region (chr10:89717747-89717771) in HBV-producing HepAD38/tetracycline-off cells, with chr10:89717756 emerging as a critical site where HBV suppresses m5C enrichment and PTEN expression. Mechanistically, the m5C “writer” NOP2/Sun RNA methyltransferase 2 (NSUN2) and the “reader” Y-box binding protein 1 (YBX1) stabilized PTEN mRNA in an m5C-dependent manner. HBV disrupted this pathway, decreasing PTEN mRNA stability via NSUN2- and YBX1-mediated m5C. Overexpression of NSUN2 or YBX1 attenuated HBV-driven proliferation, migration, and invasion, and these effects were partially reversed by the PTEN inhibitor VO-Ohpic. The small hepatitis B surface antigen and hepatitis B X protein downregulated NSUN2 and YBX1, linking viral proteins to PTEN suppression. Further, HBV is associated with reduced NSUN2 expression in HBV transgenic (HBV-Tg) mice, HBV-infected primary human hepatocytes as well as HBV-positive clinical HCC specimens, supporting the physiological and clinical relevance of this finding. Together, these findings identify the NSUN2/YBX1/PTEN axis as a potential therapeutic target in HBV-associated HCC.
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      Hepatitis B virus promotes hepatocellular carcinoma progression by disrupting NSUN2/YBX1-mediated m5C modification of PTEN mRNA

        Corresponding author: Shuxiang Wu, wushuxiang@fjmu.edu.cn
        Corresponding author: Xu Lin, linxu@fjmu.edu.cn
      • a. Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou, China;
      • b. Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou, China
      • Received Date: 03 September 2025
      • Accepted Date: 06 March 2026

      Abstract: Hepatitis B virus (HBV) has been implicated in hepatocellular carcinoma (HCC) progression, partly through regulation of the tumor suppressor phosphatase and tensin homolog (PTEN). Although transcriptional regulation of PTEN by HBV is well characterized, its post-transcriptional regulation remains poorly understood. Because RNA 5-methylcytosine (m5C) modification influences post-transcriptional gene control and cancer development, we investigated whether HBV modulates PTEN through m5C. Methylated RNA immunoprecipitation (MeRIP)-quantitative polymerase chain reaction showed a marked reduction in m5C on PTEN mRNA in HBV-producing cells. MeRIP sequencing further identified decreased m5C within the PTEN coding sequence region (chr10:89717747-89717771) in HBV-producing HepAD38/tetracycline-off cells, with chr10:89717756 emerging as a critical site where HBV suppresses m5C enrichment and PTEN expression. Mechanistically, the m5C “writer” NOP2/Sun RNA methyltransferase 2 (NSUN2) and the “reader” Y-box binding protein 1 (YBX1) stabilized PTEN mRNA in an m5C-dependent manner. HBV disrupted this pathway, decreasing PTEN mRNA stability via NSUN2- and YBX1-mediated m5C. Overexpression of NSUN2 or YBX1 attenuated HBV-driven proliferation, migration, and invasion, and these effects were partially reversed by the PTEN inhibitor VO-Ohpic. The small hepatitis B surface antigen and hepatitis B X protein downregulated NSUN2 and YBX1, linking viral proteins to PTEN suppression. Further, HBV is associated with reduced NSUN2 expression in HBV transgenic (HBV-Tg) mice, HBV-infected primary human hepatocytes as well as HBV-positive clinical HCC specimens, supporting the physiological and clinical relevance of this finding. Together, these findings identify the NSUN2/YBX1/PTEN axis as a potential therapeutic target in HBV-associated HCC.

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