Serving the Society Since 1986
Advanced Search
Volume 41 Issue 3
June 2026
    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
    shu

    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.
    • 加载中

      1. Akula, S.M., Abrams, S.L., Steelman, L.S., Emma, M.R., Augello, G., Cusimano, A., Azzolina, A., Montalto, G., Cervello, M.,Mccubrey, J.A., 2019. RAS/RAF/MEK/ERK, PI3K/PTEN/AKT/mTORC1 and TP53 pathways and regulatory miRs as therapeutic targets in hepatocellular carcinoma. Expert Opin Ther Targets, 23, 915-929.

      2. Alvarez-Garcia, V., Tawil, Y., Wise, H.M.,Leslie, N.R., 2019. Mechanisms of PTEN loss in cancer: It's all about diversity. Semin Cancer Biol, 59, 66-79.

      3. Chen, D., Gu, X., Nurzat, Y., Xu, L., Li, X., Wu, L., Jiao, H., Gao, P., Zhu, X., Yan, D., Li, S.,Xue, C., 2024. Writers, readers, and erasers RNA modifications and drug resistance in cancer. Mol Cancer, 23, 178.

      4. Chen, X., Li, A., Sun, B.F., Yang, Y., Han, Y.N., Yuan, X., Chen, R.X., Wei, W.S., Liu, Y., Gao, C.C., et al., 2019. 5-methylcytosine promotes pathogenesis of bladder cancer through stabilizing mRNAs. Nat Cell Biol, 21, 978-990.

      5. Chen, Y., Zuo, X., Wei, Q., Xu, J., Liu, X., Liu, S., Wang, H., Luo, Q., Wang, Y., Yang, Y., Zhao, H., Xu, J., Liu, T.,Yi, P., 2023. Upregulation of LRRC8A by m(5)C modification-mediated mRNA stability suppresses apoptosis and facilitates tumorigenesis in cervical cancer. Int J Biol Sci, 19, 691-704.

      6. Chen, Y.S., Yang, W.L., Zhao, Y.L.,Yang, Y.G., 2021. Dynamic transcriptomic m(5) C and its regulatory role in RNA processing. Wiley Interdiscip Rev RNA, 12, e1639.

      7. Chung, C.Y., Sun, C.P., Tao, M.H., Wu, H.L., Wang, S.H., Yeh, S.H., Zheng, Q.B., Yuan, Q., Xia, N.S., Ogawa, K., Nakashima, K., Suzuki, T.,Chen, P.J., 2024. Major HBV splice variant encoding a novel protein important for infection. J Hepatol, 80, 858-867.

      8. Chung, T.W., Lee, Y.C., Ko, J.H.,Kim, C.H., 2003. Hepatitis B Virus X protein modulates the expression of PTEN by inhibiting the function of p53, a transcriptional activator in liver cells. Cancer Res, 63, 3453-3458.

      9. Courtney, D.G., Tsai, K., Bogerd, H.P., Kennedy, E.M., Law, B.A., Emery, A., Swanstrom, R., Holley, C.L.,Cullen, B.R., 2019. Epitranscriptomic Addition of m(5)C to HIV-1 Transcripts Regulates Viral Gene Expression. Cell Host Microbe, 26, 217-227.e216.

      10. Delphin, M., Mohammed, K.S., Downs, L.O., Lumley, S.F., Waddilove, E., Okanda, D., Aliyan, N., Van Schalkwyk, M., Anderson, M., Ocama, P., Maponga, T., Torimiro, J., Iwuji, C., Ndung'u, T., Matthews, P.C.,Taljaard, J., 2024. Under-representation of the WHO African region in clinical trials of interventions against hepatitis B virus infection. Lancet Gastroenterol Hepatol, 9, 383-392.

      11. Ding, M., Wu, J., Sun, R., Yan, L., Bai, L., Shi, J., Feng, H., Zhang, Y., Lan, K.,Wang, X., 2021. Androgen receptor transactivates KSHV noncoding RNA PAN to promote lytic replication-mediated oncogenesis: A mechanism of sex disparity in KS. PLoS Pathog, 17, e1009947.

      12. Ding, S., Liu, H., Liu, L., Ma, L., Chen, Z., Zhu, M., Liu, L., Zhang, X., Hao, H., Zuo, L., Yang, J., Wu, X., Zhou, P., Huang, F., Zhu, F.,Guan, W., 2024. Epigenetic addition of m(5)C to HBV transcripts promotes viral replication and evasion of innate antiviral responses. Cell Death Dis, 15, 39.

      13. Fan, W., Liu, P., Tan, L., Lv, H., Zhou, H., Tao, Z.,Xu, Y., 2024. Tet2 modulates M2 macrophage polarization via mRNA 5-methylcytosine in allergic rhinitis. Int Immunopharmacol, 143, 113495.

      14. Feng, J., Xu, T., He, M., Li, J., Yao, P., Ma, C., Yang, S., Xu, Z., Yan, K., Chen, X., Wang, H., Liu, J., Zeng, C., Xia, Y., Yan, H., Zhou, L.,Chen, Y., 2023. NSUN2-mediated m5C modification of HBV RNA positively regulates HBV replication. PLoS Pathog, 19, e1011808.

      15. Fu, X., Song, X., Li, Y., Tan, D.,Liu, G., 2016. Hepatitis B virus X protein upregulates DNA methyltransferase 3A/3B and enhances SOCS-1CpG island methylation. Mol Med Rep, 13, 301-308.

      16. Fung, S., Choi, H.S.J., Gehring, A.,Janssen, H.L.A., 2022. Getting to HBV cure: The promising paths forward. Hepatology, 76, 233-250.

      17. Gonskikh, Y., Tirrito, C., Bommisetti, P., Mendoza-Figueroa, M.S., Stoute, J., Kim, J., Wang, Q., Song, Y.,Liu, K.F., 2025. Spatial regulation of NSUN2-mediated tRNA m5C installation in cognitive function. Nucleic Acids Res, 53, gkae1169.

      18. Guan, H., Zhu, N., Tang, G., Du, Y., Wang, L.,Yuan, W., 2022. DNA methyltransferase 1 knockdown reverses PTEN and VDR by mediating demethylation of promoter and protects against renal injuries in hepatitis B virus-associated glomerulonephritis. Cell Biosci, 12, 98.

      19. Guo, G., Pan, K., Fang, S., Ye, L., Tong, X., Wang, Z., Xue, X.,Zhang, H., 2021. Advances in mRNA 5-methylcytosine modifications: Detection, effectors, biological functions, and clinical relevance. Mol Ther Nucleic Acids, 26, 575-593.

      20. Hamamoto, H., Maemura, K., Matsuo, K., Taniguchi, K., Tanaka, Y., Futaki, S., Takeshita, A., Asai, A., Hayashi, M., Hirose, Y., Kondo, Y.,Uchiyama, K., 2018. Delta-like 3 is silenced by HBx via histone acetylation in HBV-associated HCCs. Sci Rep, 8, 4842.

      21. He, Y.F., Li, B.Z., Li, Z., Liu, P., Wang, Y., Tang, Q., Ding, J., Jia, Y., Chen, Z., Li, L., Sun, Y., Li, X., Dai, Q., Song, C.X., Zhang, K., He, C.,Xu, G.L., 2011. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNA. Science, 333, 1303-1307.

      22. Hong, X., Bianchini, E.N., Wang, J.C.,Hu, J., 2023. Characterization of Intracellular Precore-Derived Proteins and Their Functions in Hepatitis B Virus-Infected Human Hepatocytes. mBio, 14, e0350122.

      23. Huang, F., Guo, J., Zhao, N., Hou, M., Gai, X., Yang, S., Cai, P., Wang, Y., Ma, Q., Zhao, Q., et al., 2024. PTEN deficiency potentiates HBV-associated liver cancer development through augmented GP73/GOLM1. J Transl Med, 22, 254.

      24. Huang, S., Cao, C., Tang, D., Liu, Y., Zhou, W., Liu, L., Zheng, X., He, Q.,Wang, A., 2024. NSUN2 Promotes Head and Neck Squamous Cell Carcinoma Progression by Targeting EMT-Related Gene LAMC2 in an m(5)C-YBX1-Dependent Manner. Biomedicines, 12, 2533.

      25. Ito, S., Shen, L., Dai, Q., Wu, S.C., Collins, L.B., Swenberg, J.A., He, C.,Zhang, Y., 2011. Tet proteins can convert 5-methylcytosine to 5-formylcytosine and 5-carboxylcytosine. Science, 333, 1300-1303.

      26. Jeng, W.J., Papatheodoridis, G.V.,Lok, A.S.F., 2023. Hepatitis B. Lancet, 401, 1039-1052.

      27. Jin, Z., Feng, H., Liang, J., Jing, X., Zhao, Q., Zhan, L., Shen, B., Cheng, X., Su, L.,Qiu, W., 2020. FGFR3(△7-9) promotes tumor progression via the phosphorylation and destabilization of ten-eleven translocation-2 in human hepatocellular carcinoma. Cell Death Dis, 11, 903.

      28. Karoui, M., Tresallet, C., Julie, C., Zimmermann, U., Staroz, F., Brams, A., Muti, C., Boulard, C., Robreau, A.M., Puy, H., et al., 2004. Loss of heterozygosity on 10q and mutational status of PTEN and BMPR1A in colorectal primary tumours and metastases. Br J Cancer, 90, 1230-1234.

      29. Kim, D., Langmead, B.,Salzberg, S.L., 2015. HISAT: a fast spliced aligner with low memory requirements. Nat Methods, 12, 357-360.

      30. Kim, G.W., Imam, H., Khan, M., Mir, S.A., Kim, S.J., Yoon, S.K., Hur, W.,Siddiqui, A., 2021. HBV-Induced Increased N6 Methyladenosine Modification of PTEN RNA Affects Innate Immunity and Contributes to HCC. Hepatology, 73, 533-547.

      31. Li, J., Huang, Y., Yang, X., Zhou, Y.,Zhou, Y., 2018. RNAm5Cfinder: A Web-server for Predicting RNA 5-methylcytosine (m5C) Sites Based on Random Forest. Sci Rep, 8, 17299.

      32. Li, Y., Tsang, C.K., Wang, S., Li, X.X., Yang, Y., Fu, L., Huang, W., Li, M., Wang, H.Y.,Zheng, X.F., 2016. MAF1 suppresses AKT-mTOR signaling and liver cancer through activation of PTEN transcription. Hepatology, 63, 1928-1942.

      33. Li, Y., Xue, M., Deng, X., Dong, L., Nguyen, L.X.T., Ren, L., Han, L., Li, C., Xue, J., Zhao, Z., et al., 2023. TET2-mediated mRNA demethylation regulates leukemia stem cell homing and self-renewal. Cell Stem Cell, 30, 1072-1090.e1010.

      34. Liang, Z., Ye, H., Ma, J., Wei, Z., Wang, Y., Zhang, Y., Huang, D., Song, B., Meng, J., Rigden, D.J.,Chen, K., 2024. m6A-Atlas v2.0: updated resources for unraveling the N6-methyladenosine (m6A) epitranscriptome among multiple species. Nucleic Acids Res, 52, D194-D202.

      35. Lin, Y.J., Huang, L.R., Yang, H.C., Tzeng, H.T., Hsu, P.N., Wu, H.L., Chen, P.J.,Chen, D.S., 2010. Hepatitis B virus core antigen determines viral persistence in a C57BL/6 mouse model. Proc Natl Acad Sci U S A, 107, 9340-9345.

      36. Liu, J., Jiang, J., Mo, J., Liu, D., Cao, D., Wang, H., He, Y.,Wang, H., 2019. Global DNA 5-Hydroxymethylcytosine and 5-Formylcytosine Contents Are Decreased in the Early Stage of Hepatocellular Carcinoma. Hepatology, 69, 196-208.

      37. Liu, X., Wei, Q., Yang, C., Zhao, H., Xu, J., Mobet, Y., Luo, Q., Yang, D., Zuo, X., Chen, N., Yang, Y., Li, L., Wang, W., Yu, J., Xu, J., Liu, T.,Yi, P., 2024. RNA m(5)C modification upregulates E2F1 expression in a manner dependent on YBX1 phase separation and promotes tumor progression in ovarian cancer. Exp Mol Med, 56, 600-615.

      38. Liu, Y., Shen, Y., Wang, H., Zhang, Y.,Zhu, X., 2022a. m5Cpred-XS: A New Method for Predicting RNA m5C Sites Based on XGBoost and SHAP. Front Genet, 13, 853258.

      39. Liu, Y., Wang, J., Chen, J., Wu, S., Zeng, X., Xiong, Q., Guo, Y., Sun, J., Song, F., Xu, J., Yuan, S., Li, C., He, Y., Wang, M., Chen, L., Shi, Y.B., Guo, M., Guo, D.,Sun, G., 2022b. Upregulation of miR-520c-3p via hepatitis B virus drives hepatocellular migration and invasion by the PTEN/AKT/NF-κB axis. Mol Ther Nucleic Acids, 29, 47-63.

      40. Liu, Z., Wang, J., Liu, L., Yuan, H., Bu, Y., Feng, J., Liu, Y., Yang, G., Zhao, M., Yuan, Y., Zhang, H., Yun, H.,Zhang, X., 2020. Chronic ethanol consumption and HBV induce abnormal lipid metabolism through HBx/SWELL1/arachidonic acid signaling and activate Tregs in HBV-Tg mice. Theranostics, 10, 9249-9267.

      41. Lv, H., Zhang, Z.M., Li, S.H., Tan, J.X., Chen, W.,Lin, H., 2020. Evaluation of different computational methods on 5-methylcytosine sites identification. Brief Bioinform, 21, 982-995.

      42. Lv, Z., Liu, L., You, J., Zhou, P., Su, Y., Zhao, K., Zhang, J.,Zhu, F., 2024. Small HBV surface antigen drives regorafenib resistance in HCC via KIAA1429-dependent m6A modification of CCR9. J Med Virol, 96, e29894.

      43. Ma, S., Qin, K., Ouyang, H., Zhu, H., Lei, P.,Shen, G., 2020. HBV infection exacerbates PTEN defects in hepatocellular carcinoma through upregulation of miR-181a/382/362/19a. Am J Transl Res, 12, 3780-3791.

      44. Meng, H., Miao, H., Zhang, Y., Chen, T., Yuan, L., Wan, Y., Jiang, Y., Zhang, L.,Cheng, W., 2024. YBX1 promotes homologous recombination and resistance to platinum-induced stress in ovarian cancer by recognizing m5C modification. Cancer Lett, 597, 217064.

      45. Nassif, N.T., Lobo, G.P., Wu, X., Henderson, C.J., Morrison, C.D., Eng, C., Jalaludin, B.,Segelov, E., 2004. PTEN mutations are common in sporadic microsatellite stable colorectal cancer. Oncogene, 23, 617-628.

      46. Nguyen, M.H., Wong, G., Gane, E., Kao, J.H.,Dusheiko, G., 2020. Hepatitis B Virus: Advances in Prevention, Diagnosis, and Therapy. Clin Microbiol Rev, 33, e00046-19.

      47. Perez-Ramirez, C., Canadas-Garre, M., Molina, M., Faus-Dader, M.J.,Calleja-Hernandez, M., 2015. PTEN and PI3K/AKT in non-small-cell lung cancer. Pharmacogenomics, 16, 1843-1862.

      48. Revill, P.A., Tu, T., Netter, H.J., Yuen, L.K.W., Locarnini, S.A.,Littlejohn, M., 2020. The evolution and clinical impact of hepatitis B virus genome diversity. Nat Rev Gastroenterol Hepatol, 17, 618-634.

      49. Reynolds-Cortez, V., Criado-Alvarez, J.J., Martinez-Vizcaino, V., Pascual-Morena, C., Salinas-Vilca, A.,Sequi-Dominguez, I., 2024. The Effectiveness and Sero-Immunity of Hepatitis B Vaccination in People Who Use Drugs: A Systematic Review and Meta-Analysis. Vaccines (Basel), 12, 1026.

      50. Roquid, K.a.R., Alcantara, K.M.M.,Garcia, R.L., 2020. Identification and validation of mRNA 3'untranslated regions of DNMT3B and TET3 as novel competing endogenous RNAs of the tumor suppressor PTEN. Int J Oncol, 56, 544-558.

      51. Selmi, T., Hussain, S., Dietmann, S., Heiss, M., Borland, K., Flad, S., Carter, J.M., Dennison, R., Huang, Y.L., Kellner, S., Bornelov, S.,Frye, M., 2021. Sequence- and structure-specific cytosine-5 mRNA methylation by NSUN6. Nucleic Acids Res, 49, 1006-1022.

      52. Song, D., An, K., Zhai, W., Feng, L., Xu, Y., Sun, R., Wang, Y., Yang, Y.G., Kan, Q.,Tian, X., 2023. NSUN2-mediated mRNA m(5)C Modification Regulates the Progression of Hepatocellular Carcinoma. Genomics Proteomics Bioinformatics, 21, 823-833.

      53. Su, J., Wu, G., Ye, Y., Zhang, J., Zeng, L., Huang, X., Zheng, Y., Bai, R., Zhuang, L., Li, M., et al., 2021. NSUN2-mediated RNA 5-methylcytosine promotes esophageal squamous cell carcinoma progression via LIN28B-dependent GRB2 mRNA stabilization. Oncogene, 40, 5814-5828.

      54. Su, P.A., Chang, C.H., Yen, S.B., Wu, H.Y., Tung, W.J., Hu, Y.P., Chen, Y.I., Lin, M.H., Shih, C., Chen, P.J.,Tsai, K., 2024. Epitranscriptomic cytidine methylation of the hepatitis B viral RNA is essential for viral reverse transcription and particle production. Proc Natl Acad Sci U S A, 121, e2400378121.

      55. Sun, Y., Yu, M., Qu, M., Ma, Y., Zheng, D., Yue, Y., Guo, S., Tang, L., Li, G., Zheng, W., Wang, M., Guo, D.,Li, C., 2020. Hepatitis B virus-triggered PTEN/β-catenin/c-Myc signaling enhances PD-L1 expression to promote immune evasion. Am J Physiol Gastrointest Liver Physiol, 318, G162-G173.

      56. Tang, J., Xiao, X., Jiang, Y., Tian, Y., Peng, Z., Yang, M., Xu, Z.,Gong, G., 2020. miR-3 Encoded by Hepatitis B Virus Downregulates PTEN Protein Expression and Promotes Cell Proliferation. J Hepatocell Carcinoma, 7, 257-269.

      57. Wang, D., Fu, B.,Wei, H., 2022. Advances in Immunotherapy for Hepatitis B. Pathogens, 11.

      58. Wang, D.Y., Zou, L.P., Liu, X.J., Zhu, H.G.,Zhu, R., 2015. Hepatitis B virus X protein induces the histone H3 lysine 9 trimethylation on the promoter of p16 gene in hepatocarcinogenesis. Exp Mol Pathol, 99, 399-408.

      59. Wang, H., Liu, H., Chen, K., Xiao, J., He, K., Zhang, J.,Xiang, G., 2012. SIRT1 promotes tumorigenesis of hepatocellular carcinoma through PI3K/PTEN/AKT signaling. Oncol Rep, 28, 311-318.

      60. Wang, J., Shen, T., Huang, X., Kumar, G.R., Chen, X., Zeng, Z., Zhang, R., Chen, R., Li, T., Zhang, T., et al., 2016. Serum hepatitis B virus RNA is encapsidated pregenome RNA that may be associated with persistence of viral infection and rebound. J Hepatol, 65, 700-710.

      61. Wang, Y., Wei, J., Feng, L., Li, O., Huang, L., Zhou, S., Xu, Y., An, K., Zhang, Y., Chen, R., et al., 2023. Aberrant m5C hypermethylation mediates intrinsic resistance to gefitinib through NSUN2/YBX1/QSOX1 axis in EGFR-mutant non-small-cell lung cancer. Mol Cancer, 22, 81.

      62. Weng, H., Huang, H., Wu, H., Qin, X., Zhao, B.S., Dong, L., Shi, H., Skibbe, J., Shen, C., Hu, C., et al., 2018. METTL14 Inhibits Hematopoietic Stem/Progenitor Differentiation and Promotes Leukemogenesis via mRNA m(6)A Modification. Cell Stem Cell, 22, 191-205.e199.

      63. Worby, C.A.,Dixon, J.E., 2014. PTEN. Annu Rev Biochem, 83, 641-669.

      64. Wu, H., Goel, V.,Haluska, F.G., 2003. PTEN signaling pathways in melanoma. Oncogene, 22, 3113-3122.

      65. Wu, M.H., Ma, W.L., Hsu, C.L., Chen, Y.L., Ou, J.H., Ryan, C.K., Hung, Y.C., Yeh, S.,Chang, C., 2010. Androgen receptor promotes hepatitis B virus-induced hepatocarcinogenesis through modulation of hepatitis B virus RNA transcription. Sci Transl Med, 2, 32ra35.

      66. Wu, S., Ye, S., Lin, X., Chen, Y., Zhang, Y., Jing, Z., Liu, W., Chen, W., Lin, X.,Lin, X., 2021. Small hepatitis B virus surface antigen promotes malignant progression of hepatocellular carcinoma via endoplasmic reticulum stress-induced FGF19/JAK2/STAT3 signaling. Cancer Lett, 499, 175-187.

      67. Wu, Y., Ren, L., Mao, C., Shen, Z., Zhu, W., Su, Z., Lin, X.,Lin, X., 2024. Small hepatitis B virus surface antigen (SHBs) induces dyslipidemia by suppressing apolipoprotein-AII expression through ER stress-mediated modulation of HNF4α and C/EBPγ. J Virol, 98, e0123924.

      68. Xie, Q., Chen, L., Shan, X., Shan, X., Tang, J., Zhou, F., Chen, Q., Quan, H., Nie, D., Zhang, W., Huang, A.L.,Tang, N., 2014. Epigenetic silencing of SFRP1 and SFRP5 by hepatitis B virus X protein enhances hepatoma cell tumorigenicity through Wnt signaling pathway. Int J Cancer, 135, 635-646.

      69. Xing, H., Gu, X., Liu, Y., Xu, L., He, Y.,Xue, C., 2024. NSUN2 regulates Wnt signaling pathway depending on the m5C RNA modification to promote the progression of hepatocellular carcinoma. Oncogene, 43, 3469-3482.

      70. Yang, H., Wang, Y., Xiang, Y., Yadav, T., Ouyang, J., Phoon, L., Zhu, X., Shi, Y., Zou, L.,Lan, L., 2022. FMRP promotes transcription-coupled homologous recombination via facilitating TET1-mediated m5C RNA modification demethylation. Proc Natl Acad Sci U S A, 119, e2116251119.

      71. Yang, L., Pei, R.J., Li, H., Ma, X.N., Zhou, Y., Zhu, F.H., He, P.L., Tang, W., Zhang, Y.C., Xiong, J., Xiao, S.Q., Tong, X.K., Zhang, B.,Zuo, J.P., 2021. Identification of SARS-CoV-2 entry inhibitors among already approved drugs. Acta Pharmacol Sin, 42, 1347-1353.

      72. Yang, X., Yang, Y., Sun, B.F., Chen, Y.S., Xu, J.W., Lai, W.Y., Li, A., Wang, X., Bhattarai, D.P., Xiao, W., et al., 2017. 5-methylcytosine promotes mRNA export - NSUN2 as the methyltransferase and ALYREF as an m(5)C reader. Cell Res, 27, 606-625.

      73. Zhai, C.T., Tian, Y.C., Tang, Z.X.,Shao, L.J., 2021. RNA methyltransferase NSUN2 promotes growth of hepatocellular carcinoma cells by regulating fizzy-related-1 in vitro and in vivo. Kaohsiung J Med Sci, 37, 991-999.

      74. Zhang, B., Zhang, X., Jin, M., Hu, L., Zang, M., Qiu, W., Wang, S., Liu, B., Liu, S.,Guo, D., 2019. CagA increases DNA methylation and decreases PTEN expression in human gastric cancer. Mol Med Rep, 19, 309-319.

      75. Zhang, R.K., Li, Y., Sun, F.L., Zhou, Z.H., Xie, Y.X., Liu, W.J., Wang, W., Qiu, J.G., Jiang, B.H.,Wang, L., 2024. RNA methyltransferase NSUN2-mediated m5C methylation promotes Cr(VI)-induced malignant transformation and lung cancer by accelerating metabolism reprogramming. Environ Int, 192, 109055.

      76. Zhang, X., An, K., Ge, X., Sun, Y., Wei, J., Ren, W., Wang, H., Wang, Y., Du, Y., He, L., Li, O., Zhou, S., Shi, Y., Ren, T., Yang, Y.G., Kan, Q.,Tian, X., 2024. NSUN2/YBX1 promotes the progression of breast cancer by enhancing HGH1 mRNA stability through m(5)C methylation. Breast Cancer Res, 26, 94.

      77. Zheng, Q., Hou, J., Zhou, Y., Li, Z.,Cao, X., 2017. The RNA helicase DDX46 inhibits innate immunity by entrapping m(6)A-demethylated antiviral transcripts in the nucleus. Nat Immunol, 18, 1094-1103.

      78. Zhou, J.,Li, X., 2018. Association of PTEN expression with liver function and inflammatory changes in patients with liver cancer after chemotherapy. Oncol Lett, 16, 6633-6637.

      79. Zhu, Y.Z., Zhu, R., Shi, L.G., Mao, Y., Zheng, G.J., Chen, Q.,Zhu, H.G., 2010. Hepatitis B virus X protein promotes hypermethylation of p16(INK4A) promoter through upregulation of DNA methyltransferases in hepatocarcinogenesis. Exp Mol Pathol, 89, 268-275.

    • 加载中

    Figures(1)

    PDF

    Article Metrics

    Article views(26) PDF downloads(0) Cited by()

    Related
    Proportional views

      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.

        HTML

      Figure (1)  Reference (79) Relative (20)

      目录

      This journal is a member of, and subscribes to the principles of, the Committee on Publication Ethics (COPE)

      鄂ICP备05001977号

         

      鄂公网安备 42010602003674号

      Copyright © 2019 Virologica Sinica. All rights reserved

      /

      DownLoad:  Full-Size Img  PowerPoint
      Return
      Return