Mechanisms and application progress of hepatitis B virus RNA in hepatocellular carcinoma_West China Medical Journal

Authors：

LIU Xiaohua ¹ , ZHANG Linyan ¹ , HUANG Huacui ¹ ,  XU Ying ²

1. Department of Medical Laboratory, Xindu District People’s Hospital of Chengdu, Chengdu, Sichuan 610500, P. R. China;
2. Department of Clinical Laboratory, the First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, P. R. China;

Corresponding?author：

XU Ying, Email: yingxu825@126.com

Keywords：

Hepatitis B virus RNA; hepatocellular carcinoma; mechanism; application

DOI：

10.7507/1002-0179.202508053

Video：

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Hepatitis B virus (HBV) RNA, as a novel biomarker, not only participates in viral replication and infection processes but may also promote the formation of hepatocellular carcinoma (HCC) by influencing hepatocyte proliferation, apoptosis, and the liver microenvironment. However, the specific mechanisms of HBV RNA remain inadequately summarized and thoroughly explored. This article systematically reviews the biological characteristics of HBV RNA and its mechanisms and applications in HCC, aiming to provide a foundation for future research and clinical diagnosis and treatment in HCC.

Citation： LIU Xiaohua, ZHANG Linyan, HUANG Huacui, XU Ying. Mechanisms and application progress of hepatitis B virus RNA in hepatocellular carcinoma. West China Medical Journal, 2026, 41(6): 1027-1031. doi: 10.7507/1002-0179.202508053 Copy

1.	Pol S. Hepatocellular carcinoma (HCC). Med Trop Sante Int, 2024, 4(4): mtsi.v4i4.2024.614.
2.	Chakraborty E, Sarkar D. Emerging therapies for hepatocellular carcinoma (HCC). Cancers (Basel), 2022, 14(11): 2798.
3.	Liu T, Song C, Zhang Y, et al. Hepatitis B virus infection and the risk of gastrointestinal cancers among Chinese population: a prospective cohort study. Int J Cancer, 2022, 150(6): 1018-1028.
4.	Liu D, Luo Y, Chen L, et al. Diagnostic value of 5 serum biomarkers for hepatocellular carcinoma with different epidemiological backgrounds: a large-scale, retrospective study. Cancer Biol Med, 2021, 18(1): 256-270.
5.	Lim HC, Gordan JD. Tumor hepatitis B virus RNA identifies a clinically and molecularly distinct subset of hepatocellular carcinoma. PLoS Comput Biol, 2021, 17(2): e1008699.
6.	Tu W, Gong J, Tian D, et al. Hepatitis B virus X protein induces SATB1 expression through activation of ERK and p38MAPK pathways to suppress anoikis. Dig Dis Sci, 2019, 64(11): 3203-3214.
7.	Chen W, Desert R, Ge X, et al. The matrisome genes from hepatitis B-related hepatocellular carcinoma unveiled. Hepatol Commun, 2021, 5(9): 1571-1585.
8.	Fernandes da Silva C, Keeshan A, Cooper C. Hepatitis B virus genotypes influence clinical outcomes: a review. Can Liver J, 2023, 6(3): 347-352.
9.	Liu S, Deng R, Zhou B, et al. Association of serum hepatitis B virus rna with hepatocellular carcinoma risk in chronic hepatitis B patients under nucleos(t)ide analogues therapy. J Infect Dis, 2022, 226(5): 881-890.
10.	劉小花, 余楊, 王桂香, 等. 血清 HBV RNA 分子特征、檢測方法及臨床應用研究. 國際檢驗醫學雜志, 2024, 45(22): 2805-2808, 2816.
11.	李德瑤, 陸丹娟, 曲晨簫, 等. 乙型肝炎病毒 RNA 的轉錄后調控機制及抗病毒策略. 中華肝臟病雜志, 2024, 32(5): 474-480.
12.	Olenginski LT, Kasprzak WK, Bergonzo C, et al. Conformational dynamics of the hepatitis B virus pre-genomic RNA on multiple time scales: implications for viral replication. J Mol Biol, 2022, 434(18): 167633.
13.	Wu Y, Wen J, Xiao W, et al. Pregenomic RNA: how to assist the management of chronic hepatitis B?. Rev Med Virol, 2019, 29(4): e2051.
14.	Lin YH, Lai MW, Yeh CT, et al. Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression. Cancer Cell Int, 2025, 25(1): 224.
15.	Mao R, Dong M, Shen Z, et al. RNA helicase DDX17 inhibits hepatitis B virus replication by blocking viral pregenomic RNA encapsidation. J Virol, 2021, 95(19): e0044421.
16.	Shen S, Xie Z, Cai D, et al. Biogenesis and molecular characteristics of serum hepatitis B virus RNA. PLoS Pathog, 2020, 16(10): e1008945.
17.	Zhu SJ, Li YH, Wang QT, et al. Circulating hepatitis B virus RNA in newborns from carrier mothers. Intervirology, 2007, 50(3): 209-213.
18.	Garcia-Garcia S, Cortese MF, Tabernero D, et al. Cross-sectional evaluation of circulating hepatitis B virus RNA and DNA: different quasispecies?. World J Gastroenterol, 2021, 27(41): 7144-7158.
19.	Matsuda S, Maekawa S, Komiyama Y, et al. Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy. Hepatol Res, 2021, 51(1): 39-50.
20.	Heise T, Guidotti LG, Chisari FV. Characterization of nuclear RNases that cleave hepatitis B virus RNA near the La protein binding site. J Virol, 2001, 75(15): 6874-6883.
21.	Ma C, Xu W, Yang Q, et al. Osteopetrosis-associated transmembrane protein 1 recruits RNA exosome to restrict hepatitis B virus replication. J Virol, 2020, 94(11): e01800-19.
22.	Shin HJ, Kim SS, Cho YH, et al. Host cell proteins binding to the encapsidation signal epsilon in hepatitis B virus RNA. Arch Virol, 2002, 147(3): 471-491.
23.	Kumada T, Toyoda H, Yasuda S, et al. Hepatitis B virus RNA predicts hepatocellular carcinoma despite viral suppression. Aliment Pharmacol Ther, 2026, 63(8): 1089-1098.
24.	Pollicino T, Caminiti G. HBV-integration studies in the clinic: role in the natural history of infection. Viruses, 2021, 13(3): 368.
25.	Turton KL, Meier-Stephenson V, Badmalia MD, et al. host transcription factors in hepatitis B virus RNA synthesis. Viruses, 2020, 12(2): 160.
26.	Cariani E, Lasserre C, Kemeny F, et al. Expression of insulin-like growth factor II, alpha-fetoprotein and hepatitis B virus transcripts in human primary liver cancer. Hepatology, 1991, 13(4): 644-649.
27.	Liu Z, Naz W, Yousaf T, et al. Viral-Track integrated single-cell RNA-sequencing reveals HBV lymphotropism and immunosuppressive microenvironment in HBV-associated hepatocellular carcinoma. Commun Biol, 2025, 8(1): 1030.
28.	Wang Y, Wu J, Zhang Y, et al. Elevated hepatitis B virus RNA levels in hepatocellular carcinoma patients compared to cirrhotic individuals: a propensity score matched analysis. Saudi J Gastroenterol, 2024, 30(5): 294-301.
29.	Wada M, Morita C, Ohsaki E, et al. Cell-intrinsic regulation of HBV RNAs by the nonsense-mediated mRNA decay pathway controls viral replication. iScience, 2025, 28(5): 112460.
30.	Sarfaraz N, Somarowthu S, Bouchard MJ. The interplay of long noncoding RNAs and hepatitis B virus. J Med Virol, 2023, 95(1): e28058.
31.	Yu M, Dandri M, Cheng G, et al. Rapid and reliable protein-free HBV DNA extraction and sensitive branched DNA southern blot assay. Methods Mol Biol, 2024, 2837: 113-124.
32.	Giosa D, Lombardo D, Musolino C, et al. Mitochondrial DNA is a target of HBV integration. Commun Biol, 2023, 6(1): 684.
33.	Quan W, Bello KE, Shueb RH, et al. Circular RNAs in hepatitis B virus-induced hepatocellular carcinoma: a comprehensive review and recent advances. Genes Dis, 2025, 12(5): 101605.
34.	Yang L, Wang H, Yan H, et al. (-)-Lariciresinol isolated from the roots of Isatis Indigotica Fortune ex Lindl. inhibits hepatitis B virus by regulating viral transcription. Molecules, 2022, 7(10): 3223.
35.	Kumar A, Combe E, Mougené L, et al. Applications of CRISPR/Cas as a toolbox for hepatitis B virus detection and therapeutics. Viruses, 2024, 16(10): 1565.
36.	Pastor F, Charles E, Di Vona C, et al. The dual-specificity kinase DYRK1A interacts with the hepatitis B virus genome and regulates the production of viral RNA. PLoS One, 2024, 19(10): e0311655.
37.	Ohlendorf V, Bremer B, Sandmann L, et al. Limited stability of hepatitis B virus RNA in plasma and serum. Sci Rep, 2024, 14(1): 27128.
38.	Wu L, Yang Z, Zheng M. Biogenesis of serum HBV RNA and clinical phenomena of serum HBV RNA in chronic hepatitis B patients before and after receiving nucleos(t)ide analogues therapy. J Viral Hepat, 2024, 31(5): 255-265.
39.	van Campenhout MJH, van B?mmel F, Pfefferkorn M, et al. Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B. J Viral Hepat, 2020, 27(6): 610-619.
40.	Kim SC, Wallin JJ, Ghosheh Y, et al. Efficacy of antiviral therapy and host-virus interactions visualised using serial liver sampling with fine-needle aspirates. JHEP Rep, 2023, 5(9): 100817.
41.	Morrissey DV, Lee PA, Johnson DA, et al. Characterization of nuclease-resistant ribozymes directed against hepatitis B virus RNA. J Viral Hepat, 2002, 9(6): 411-418.
42.	Sun L, Snedeker A, Tang L. A hepatitis B virus RNA-sensing and RNA-editing-dependent reporter system. J Virol, 2025, 99(11): e0092225.
43.	Zheng Y, Wang M, Yin J, et al. Hepatitis B virus RNAs co-opt ELAVL1 for stabilization and CRM1-dependent nuclear export. PLoS Pathog, 2024, 20(2): e1011999.
44.	Wang M, Chen Q, Zheng Y, et al. RANBP3 and RAN orchestrate CRM1-mediated nuclear export of hepatitis B virus RNAs. J Virol, 2026, 100(5): e0026726.
45.	Liu S, Zhou B, Valdes JD, et al. Serum hepatitis B virus RNA: a new potential biomarker for chronic hepatitis B virus infection. Hepatology, 2019, 69(4): 1816-1827.
46.	Kostyusheva A, Kostyushev D, Brezgin S, et al. Clinical implications of hepatitis B virus RNA and covalently closed circular DNA in monitoring patients with chronic hepatitis B today with a gaze into the future: the field is unprepared for a sterilizing cure. Genes (Basel), 2018, 9(10): 483.
47.	Prakash K, Larsson SB, Rydell GE, et al. Hepatitis B virus RNA profiles in liver biopsies by digital polymerase chain reaction. Hepatol Commun, 2020, 4(7): 973-982.

1. Pol S. Hepatocellular carcinoma (HCC). Med Trop Sante Int, 2024, 4(4): mtsi.v4i4.2024.614.
2. Chakraborty E, Sarkar D. Emerging therapies for hepatocellular carcinoma (HCC). Cancers (Basel), 2022, 14(11): 2798.
3. Liu T, Song C, Zhang Y, et al. Hepatitis B virus infection and the risk of gastrointestinal cancers among Chinese population: a prospective cohort study. Int J Cancer, 2022, 150(6): 1018-1028.
4. Liu D, Luo Y, Chen L, et al. Diagnostic value of 5 serum biomarkers for hepatocellular carcinoma with different epidemiological backgrounds: a large-scale, retrospective study. Cancer Biol Med, 2021, 18(1): 256-270.
5. Lim HC, Gordan JD. Tumor hepatitis B virus RNA identifies a clinically and molecularly distinct subset of hepatocellular carcinoma. PLoS Comput Biol, 2021, 17(2): e1008699.
6. Tu W, Gong J, Tian D, et al. Hepatitis B virus X protein induces SATB1 expression through activation of ERK and p38MAPK pathways to suppress anoikis. Dig Dis Sci, 2019, 64(11): 3203-3214.
7. Chen W, Desert R, Ge X, et al. The matrisome genes from hepatitis B-related hepatocellular carcinoma unveiled. Hepatol Commun, 2021, 5(9): 1571-1585.
8. Fernandes da Silva C, Keeshan A, Cooper C. Hepatitis B virus genotypes influence clinical outcomes: a review. Can Liver J, 2023, 6(3): 347-352.
9. Liu S, Deng R, Zhou B, et al. Association of serum hepatitis B virus rna with hepatocellular carcinoma risk in chronic hepatitis B patients under nucleos(t)ide analogues therapy. J Infect Dis, 2022, 226(5): 881-890.
10. 劉小花, 余楊, 王桂香, 等. 血清 HBV RNA 分子特征、檢測方法及臨床應用研究. 國際檢驗醫學雜志, 2024, 45(22): 2805-2808, 2816.
11. 李德瑤, 陸丹娟, 曲晨簫, 等. 乙型肝炎病毒 RNA 的轉錄后調控機制及抗病毒策略. 中華肝臟病雜志, 2024, 32(5): 474-480.
12. Olenginski LT, Kasprzak WK, Bergonzo C, et al. Conformational dynamics of the hepatitis B virus pre-genomic RNA on multiple time scales: implications for viral replication. J Mol Biol, 2022, 434(18): 167633.
13. Wu Y, Wen J, Xiao W, et al. Pregenomic RNA: how to assist the management of chronic hepatitis B?. Rev Med Virol, 2019, 29(4): e2051.
14. Lin YH, Lai MW, Yeh CT, et al. Perspectives on NcRNAs in HBV/cccDNA-driven HCC progression. Cancer Cell Int, 2025, 25(1): 224.
15. Mao R, Dong M, Shen Z, et al. RNA helicase DDX17 inhibits hepatitis B virus replication by blocking viral pregenomic RNA encapsidation. J Virol, 2021, 95(19): e0044421.
16. Shen S, Xie Z, Cai D, et al. Biogenesis and molecular characteristics of serum hepatitis B virus RNA. PLoS Pathog, 2020, 16(10): e1008945.
17. Zhu SJ, Li YH, Wang QT, et al. Circulating hepatitis B virus RNA in newborns from carrier mothers. Intervirology, 2007, 50(3): 209-213.
18. Garcia-Garcia S, Cortese MF, Tabernero D, et al. Cross-sectional evaluation of circulating hepatitis B virus RNA and DNA: different quasispecies?. World J Gastroenterol, 2021, 27(41): 7144-7158.
19. Matsuda S, Maekawa S, Komiyama Y, et al. Deep sequencing analysis of serum hepatitis B virus-RNA during nucleot(s)ide analogue therapy. Hepatol Res, 2021, 51(1): 39-50.
20. Heise T, Guidotti LG, Chisari FV. Characterization of nuclear RNases that cleave hepatitis B virus RNA near the La protein binding site. J Virol, 2001, 75(15): 6874-6883.
21. Ma C, Xu W, Yang Q, et al. Osteopetrosis-associated transmembrane protein 1 recruits RNA exosome to restrict hepatitis B virus replication. J Virol, 2020, 94(11): e01800-19.
22. Shin HJ, Kim SS, Cho YH, et al. Host cell proteins binding to the encapsidation signal epsilon in hepatitis B virus RNA. Arch Virol, 2002, 147(3): 471-491.
23. Kumada T, Toyoda H, Yasuda S, et al. Hepatitis B virus RNA predicts hepatocellular carcinoma despite viral suppression. Aliment Pharmacol Ther, 2026, 63(8): 1089-1098.
24. Pollicino T, Caminiti G. HBV-integration studies in the clinic: role in the natural history of infection. Viruses, 2021, 13(3): 368.
25. Turton KL, Meier-Stephenson V, Badmalia MD, et al. host transcription factors in hepatitis B virus RNA synthesis. Viruses, 2020, 12(2): 160.
26. Cariani E, Lasserre C, Kemeny F, et al. Expression of insulin-like growth factor II, alpha-fetoprotein and hepatitis B virus transcripts in human primary liver cancer. Hepatology, 1991, 13(4): 644-649.
27. Liu Z, Naz W, Yousaf T, et al. Viral-Track integrated single-cell RNA-sequencing reveals HBV lymphotropism and immunosuppressive microenvironment in HBV-associated hepatocellular carcinoma. Commun Biol, 2025, 8(1): 1030.
28. Wang Y, Wu J, Zhang Y, et al. Elevated hepatitis B virus RNA levels in hepatocellular carcinoma patients compared to cirrhotic individuals: a propensity score matched analysis. Saudi J Gastroenterol, 2024, 30(5): 294-301.
29. Wada M, Morita C, Ohsaki E, et al. Cell-intrinsic regulation of HBV RNAs by the nonsense-mediated mRNA decay pathway controls viral replication. iScience, 2025, 28(5): 112460.
30. Sarfaraz N, Somarowthu S, Bouchard MJ. The interplay of long noncoding RNAs and hepatitis B virus. J Med Virol, 2023, 95(1): e28058.
31. Yu M, Dandri M, Cheng G, et al. Rapid and reliable protein-free HBV DNA extraction and sensitive branched DNA southern blot assay. Methods Mol Biol, 2024, 2837: 113-124.
32. Giosa D, Lombardo D, Musolino C, et al. Mitochondrial DNA is a target of HBV integration. Commun Biol, 2023, 6(1): 684.
33. Quan W, Bello KE, Shueb RH, et al. Circular RNAs in hepatitis B virus-induced hepatocellular carcinoma: a comprehensive review and recent advances. Genes Dis, 2025, 12(5): 101605.
34. Yang L, Wang H, Yan H, et al. (-)-Lariciresinol isolated from the roots of Isatis Indigotica Fortune ex Lindl. inhibits hepatitis B virus by regulating viral transcription. Molecules, 2022, 7(10): 3223.
35. Kumar A, Combe E, Mougené L, et al. Applications of CRISPR/Cas as a toolbox for hepatitis B virus detection and therapeutics. Viruses, 2024, 16(10): 1565.
36. Pastor F, Charles E, Di Vona C, et al. The dual-specificity kinase DYRK1A interacts with the hepatitis B virus genome and regulates the production of viral RNA. PLoS One, 2024, 19(10): e0311655.
37. Ohlendorf V, Bremer B, Sandmann L, et al. Limited stability of hepatitis B virus RNA in plasma and serum. Sci Rep, 2024, 14(1): 27128.
38. Wu L, Yang Z, Zheng M. Biogenesis of serum HBV RNA and clinical phenomena of serum HBV RNA in chronic hepatitis B patients before and after receiving nucleos(t)ide analogues therapy. J Viral Hepat, 2024, 31(5): 255-265.
39. van Campenhout MJH, van B?mmel F, Pfefferkorn M, et al. Serum hepatitis B virus RNA predicts response to peginterferon treatment in HBeAg-positive chronic hepatitis B. J Viral Hepat, 2020, 27(6): 610-619.
40. Kim SC, Wallin JJ, Ghosheh Y, et al. Efficacy of antiviral therapy and host-virus interactions visualised using serial liver sampling with fine-needle aspirates. JHEP Rep, 2023, 5(9): 100817.
41. Morrissey DV, Lee PA, Johnson DA, et al. Characterization of nuclease-resistant ribozymes directed against hepatitis B virus RNA. J Viral Hepat, 2002, 9(6): 411-418.
42. Sun L, Snedeker A, Tang L. A hepatitis B virus RNA-sensing and RNA-editing-dependent reporter system. J Virol, 2025, 99(11): e0092225.
43. Zheng Y, Wang M, Yin J, et al. Hepatitis B virus RNAs co-opt ELAVL1 for stabilization and CRM1-dependent nuclear export. PLoS Pathog, 2024, 20(2): e1011999.
44. Wang M, Chen Q, Zheng Y, et al. RANBP3 and RAN orchestrate CRM1-mediated nuclear export of hepatitis B virus RNAs. J Virol, 2026, 100(5): e0026726.
45. Liu S, Zhou B, Valdes JD, et al. Serum hepatitis B virus RNA: a new potential biomarker for chronic hepatitis B virus infection. Hepatology, 2019, 69(4): 1816-1827.
46. Kostyusheva A, Kostyushev D, Brezgin S, et al. Clinical implications of hepatitis B virus RNA and covalently closed circular DNA in monitoring patients with chronic hepatitis B today with a gaze into the future: the field is unprepared for a sterilizing cure. Genes (Basel), 2018, 9(10): 483.
47. Prakash K, Larsson SB, Rydell GE, et al. Hepatitis B virus RNA profiles in liver biopsies by digital polymerase chain reaction. Hepatol Commun, 2020, 4(7): 973-982.

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