Chronic HBV infection, stemness pathways, and compromised immune surveillance in HCC development
Main Article Content
Keywords
OCT4, NANOG, Sox2, Hepatocellular Carcinoma, Hepatitis B virus
Abstract
Chronic hepatitis B virus (HBV) infection is a leading cause of hepatocellular carcinoma (HCC). This review elucidates the molecular pathways by which HBV promotes the expression of the stemness transcription factors OCT4, Sox2, and NANOG. Through a comprehensive literature review, we found that HBV enhances its expression via multiple mechanisms. These include HBxAg-induced chromatin remodeling, activation of histone demethylase KDM5B, and integration of the truncated HBx-ΔC protein into the host genome. Furthermore, chronic inflammation driven by persistent HBV infection acts as a key driver for their overexpression. This dysregulation is strongly associated with increased tumor proliferation, metastasis, and poor prognosis in HBV-infected HCC patients. Consequently, OCT4, Sox2, and NANOG emerge as promising biomarkers for early detection and prognosis, as well as potential therapeutic targets. Modulating their activity could offer novel strategies for targeted treatment. In conclusion, HBV-induced alterations in these transcription factors represent critical oncogenic mechanisms in HCC. Further research is essential to develop novel therapeutic approaches that regulate their activity, ultimately improving clinical outcomes for patients.
References
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2. Nahavandi-Parizi P, Kariminik A, Montazeri M. Retinoic acid-inducible gene 1 (RIG-1) and IFN-β promoter stimulator-1 (IPS-1) significantly down-regulated in the severe coronavirus disease 2019 (COVID-19). Mol Biol Rep. 2023;50(1):907–11. https://doi.org/10.1007/s11033-022-07981-2
3 Brown ZJ, Tsilimigras DI, Ruff SM, Mohseni A, Kamel IR, Cloyd JM, et al. Management of hepatocellular carcinoma: A review. JAMA Surg. 2023;158(4):410–20. https://doi.org/10.1001/jamasurg.2022.7989
4. Capasso M, Cossiga V, Guarino M, Ranieri L, Morisco F. The role of hepatitis viruses as drivers of hepatocancerogenesis. Cancers. 2024;16(8):1505. https://doi.org/10.3390/cancers16081505
5. Bahaaldin-Beygi M, Kariminik A, Arababadi MK. Royal jelly significantly alters inflammasome pathways in patients with chronic hepatitis B. IJEB. 2022;60(11):875–9. https://doi.org/10.56042/ijeb. v60i11.60264
6. Zhang M, Chen H, Liu H, Tang H. The impact of integrated hepatitis B virus DNA on oncogenesis and antiviral therapy. Biomark Res. 2024;12(1):84. https://doi.org/10.1186/s40364-024-00611-y
7. Zhou L, He L, Liu CH, Qiu H, Zheng L, Sample KM, et al. Liver cancer stem cell dissemination and metastasis: Uncovering the role of NRCAM in hepatocellular carcinoma. J Exp Clin Cancer Res. 2023;42(1):311. https://doi.org/10.1186/s13046-023-02893-w
8. Roy A, Mishra J, Chakraborty S, Singh SP, Patra SK. Epigenetic regulation of pluripotency inducer genes NANOG and SOX2 in human prostate cancer. Progress Mol Biol Transl Sci. 2023; 197:241–60. https://doi.org/10.1016/bs.pmbts.2023.01.010
9. Ye C, Zhang X, Chen X, Cao Q, Zhang X, Zhou Y, et al. Multiple novel hepatocellular carcinoma signature genes are commonly controlled by the master pluripotency factor OCT4. Cell Oncol. 2020; 43:279–95. https://doi.org/10.1007/s13402-019-00487-3
10. Ching RH, Sze KM, Lau EY, Chiu YT, Lee JM, Ng IO, et al. C-terminal truncated hepatitis B virus X protein regulates tumorigenicity, self-renewal and drug resistance via STAT3/Nanog signaling pathway. Oncotarget. 2017;8(14):23507. https://doi.org/10.18632/oncotarget.15183
11. Martins-Neves SR, Sampaio-Ribeiro G, Gomes CM. Self-renewal and pluripotency in osteosarcoma stem cells’ chemoresistance: Notch, hedgehog, and wnt/β-catenin interplay with embryonic markers. Int J Mol Sci. 2023;24(9): 8401. https://doi.org/10.3390/ijms24098401
12. Borgia M, Dal Bo M, Toffoli G. Role of virus-related chronic inflammation and mechanisms of cancer immune-suppression in pathogenesis and progression of hepatocellular carcinoma. Cancers. 2021;13(17):4387. https://doi.org/10.3390/cancers13174387
13. Tu T, Budzinska MA, Shackel NA, Urban S. HBV DNA integration: Molecular mechanisms and clinical implications. Viruses. 2017;9(4):75. https://doi.org/10.3390/v9040075
14. Li W, Wang S, Jin Y, Mu X, Guo Z, Qiao S, et al. The role of the hepatitis B virus genome and its integration in the hepatocellular carcinoma. Front Microbiol. 2024:15:1469016. https://doi.org/10.3389/fmicb.2024.1469016
15. Sze KM, Ho DW, Chiu YT, Tsui YM, Chan LK, Lee JM, et al. Hepatitis B virus–telomerase reverse transcriptase promoter integration harnesses host ELF4, resulting in telomerase reverse transcriptase gene transcription in hepatocellular carcinoma. Hepatology. 2021;73(1):23–40. https://doi.org/10.1002/hep.31231
16. Tarocchi M, Polvani S, Marroncini G, Galli A. Molecular mechanism of hepatitis B virus-induced hepatocarcinogenesis. World J Gastroenterol. 2014;20(33): 11630–40. https://doi.org/10.3748/wjg. v20.i33.11630
17. Gómez-Moreno A, Garaigorta U. Hepatitis B virus and DNA damage response: Interactions and consequences for the infection. Viruses. 2017;9(10):304. https://doi.org/10.3390/v9100304
18. Hu T, Wang J, Li W, Liu M, Han N, Yuan M, et al. Endoplasmic reticulum stress in hepatitis B virus and hepatitis C virus infection. Viruses. 2022;14(12):2630. https://doi.org/10.3390/v14122630
19. Shoraka S, Hosseinian SM, Hasibi A, Ghaemi A, Mohebbi SR. The role of hepatitis B virus genome variations in HBV-related HCC: Effects on host signaling pathways. Front Microbiol. 2023;14:1213145. https://doi.org/10.3389/fmicb.2023.1213145
20. D'souza S, Lau KC, Coffin CS, Patel TR. Molecular mechanisms of viral hepatitis induced hepatocellular carcinoma. World J Gastroenterol. 2020;26(38):5759–83. https://doi.org/10.3748/wjg. v26.i38.5759
21. Dimitriadis K, Katelani S, Pappa M, Fragkoulis GE, Androutsakos T. The role of interleukins in HBV infection: A narrative review. J Pers Med. 2023;13(12):1675. https://doi.org/10.3390/jpm13121675
22. Hou XJ, Ye F, Li XY, Liu WT, Jing YY, Han ZP, et al. Immune response involved in liver damage and the activation of hepatic progenitor cells during liver tumorigenesis.Cell Immunol. 2018;326:52–9. https://doi.org/10.1016/j.cellimm.2017.08.004
23. Daud M, Rana MA, Husnain T, Ijaz B. Modulation of Wnt signaling pathway by hepatitis B virus. Arch Virol. 2017;162(10):2937–47. https://doi.org/10.1007/s00705-017-3462-6
24. Wang R, Sun Q, Wang P, Liu M, Xiong S, Luo J, et al. Notch and Wnt/β-catenin signaling pathway play important roles in activating liver cancer stem cells. Oncotarget. 2016;7(5):5754–68. https://doi.org/10.18632/oncotarget.6805
25. Vasefifar P, Motafakkerazad R, Maleki LA, Najafi S, Ghrobaninezhad F, Najafzadeh B, et al. Nanog, as a key cancer stem cell marker in tumor progression. Gene. 2022;827:146448. https://doi.org/10.1016/j.gene.2022.146448
26. Sohn EJ, Moon HJ, Lim JK, Kim DS, Kim JH. Regulation of the protein stability and transcriptional activity of OCT4 in stem cells. Adv Biol Regul. 2021;79:100777. https://doi.org/10.1016/j.jbior.2020.100777
27. Rizzino A. Sox2 and Oct-3/4: A versatile pair of master regulators that orchestrate the self-renewal and pluripotency of embryonic stem cells. Wiley Interdiscip Rev Syst Biol Med. 2009;1(2):228–36. https://doi.org/10.1002/wsbm.12
28. Zheng YW, Nie YZ, Taniguchi H. Cellular reprogramming and hepatocellular carcinoma development. World J Gastroenterol. 2013;19(47):8850–60. https://doi.org/10.3748/wjg. v19.i47.8850
29. Liang C, Xu Y, Ge H, Li G, Wu J. Clinicopathological and prognostic significance of OCT4 in patients with hepatocellular carcinoma: A meta-analysis. Onco Targets Ther. 2018;11:47–57. https://doi.org/10.2147/OTT.S151390
30. Gordeeva O. TGFβ Family signaling pathways in pluripotent and teratocarcinoma stem cells' fate decisions: Balancing between self-renewal, differentiation, and cancer. Cells. 2019;8(12). https://doi.org/10.3390/cells8121500
31. Li W, Duan X, Zhu C, Liu X, Jeyarajan AJ, Xu M, et al. Hepatitis B and hepatitis C virus infection promote liver fibrogenesis through a TGF-β1-Induced OCT4/Nanog pathway. J Immunol. 2022;208(3):672–84. https://doi.org/10.4049/jimmunol.2001453
32. Liu Z, Dai X, Wang T, Zhang C, Zhang W, Zhang W, et al. Hepatitis B virus PreS1 facilitates hepatocellular carcinoma development by promoting appearance and self-renewal of liver cancer stem cells. Cancer Lett. 2017;400:149–60. https://doi.org/10.1016/j.canlet.2017.04.017
33. Zhu M, Li W, Lu Y, Dong X, Lin B, Chen Y, et al. HBx drives alpha fetoprotein expression to promote initiation of liver cancer stem cells through activating PI3K/AKT signal pathway. Int J Cancer. 2017;140(6):1346–55. https://doi.org/10.1002/ijc.30553
34. Arzumanyan A, Friedman T, Ng IO, Clayton MM, Lian Z, Feitelson MA. Does the hepatitis B antigen HBx promote the appearance of liver cancer stem cells? Cancer Res. 2011;71(10):3701–8. https://doi.org/10.1158/0008-5472.CAN-10-3951
35. Wang X, Oishi N, Shimakami T, Yamashita T, Honda M, Murakami S, et al. Hepatitis B virus X protein induces hepatic stem cell-like features in hepatocellular carcinoma by activating KDM5B. World J Gastroenterol. 2017;23(18):3252–61. https://doi.org/10.3748/wjg. v23.i18.3252
36. Ching RH, Sze KM, Lau EY, Chiu YT, Lee JM, Ng IO, et al. C-terminal truncated hepatitis B virus X protein regulates tumorigenicity, self-renewal and drug resistance via STAT3/Nanog signaling pathway. Oncotarget. 2017;8(14):23507–16. https://doi.org/10.18632/oncotarget.15183
37. Mani SK, Zhang H, Diab A, Pascuzzi PE, Lefrançois L, Fares N, et al. EpCAM-regulated intramembrane proteolysis induces a cancer stem cell-like gene signature in hepatitis B virus-infected hepatocytes. J Hepatol. 2016;65(5):888–98. https://doi.org/10.1016/j.jhep.2016.05.022
38. Song Y, Pan G, Chen L, Ma S, Zeng T, Chan TH, et al. Loss of ATOH8 increases stem cell features of hepatocellular carcinoma cells. Gastroenterology. 2015;149(4):1068–81 e5. https://doi.org/10.1053/j.gastro.2015.06.010
39. Chang TS, Wu YC, Chi CC, Su WC, Chang PJ, Lee KF, et al. Activation of IL6/IGFIR confers poor prognosis of HBV-related hepatocellular carcinoma through induction of OCT4/NANOG expression. Clin Cancer Res. 2015;21(1):201–10. https://doi.org/10.1158/1078-0432.CCR-13-3274
40. Gufler S, Seeboeck R, Schatz C, Haybaeck J. The translational bridge between inflammation and hepatocarcinogenesis. Cells. 2022;11(3):533. https://doi.org/10.3390/cells11030533
41. Chang TS, Chen CL, Wu YC, Liu JJ, Kuo YC, Lee KF, et al. Inflammation promotes expression of stemness-related properties in HBV-related hepatocellular carcinoma. PLoS One. 2016;11(2):e0149897. https://doi.org/10.1371/journal.pone.0149897
42. Tsukamoto H, Mishra L, Machida K. Alcohol, TLR4-TGF-β antagonism, and liver cancer. Hepatol Int. 2014;8 (2):408–12. https://doi.org/10.1007/s12072-013-9489-1
43. Xu XL, Xing BC, Han HB, Zhao W, Hu MH, Xu ZL, et al. The properties of tumor-initiating cells from a hepatocellular carcinoma patient's primary and recurrent tumor. Carcinogenesis. 2010;31(2):167–74. https://doi.org/10.1093/carcin/bgp232
44. Oliva J, French BA, Qing X, French SW. The identification of stem cells in human liver diseases and hepatocellular carcinoma. Exp Mol Pathol. 2010;88(3):331–40. https://doi.org/10.1016/j.yexmp.2010.01.003
45. Yin X, Li YW, Zhang BH, Ren ZG, Qiu SJ, Yi Y, Fan J. Coexpression of stemness factors Oct4 and Nanog predict liver resection. Ann Surg Oncol. 2012;19(9):2877–87. https://doi.org/10.1245/s10434-012-2314-6
46. Fan H, Cui Z, Zhang H, Mani SK, Diab A, Lefrancois L, et al. DNA demethylation induces SALL4 gene re-expression in subgroups of hepatocellular carcinoma associated with Hepatitis B or C virus infection. Oncogene. 2017;36(17):2435–45. https://doi.org/10.1038/onc.2016.399
47. Shin JG, Cheong HS, Lee K, Ju BG, Lee JH, Yu SJ, et al. Identification of novel OCT4 genetic variant associated with the risk of chronic hepatitis B in a Korean population. Liver Int. 2017;37(3):354–61. https://doi.org/10.1111/liv.13245
48. Sartorius K, Makarova J, Sartorius B, An P, Winkler C, Chuturgoon A, et al. The regulatory role of microrna in hepatitis-b virus-associated hepatocellular carcinoma (HBV-HCC) pathogenesis. cells. 2019;8(12). https://doi.org/10.3390/cells8121504
49. Bautista WW, Osiowy C, Klein J, Minuk GY. Hepatitis B Virus infection of normal hepatic stem/progenitor cells. J Clin Exp Hepatol. 2019;9(1):34–42. https://doi.org/10.1016/j.jceh.2018.02.002
50. Yang H, Mo J, Xiang Q, Zhao P, Song Y, Yang G, et al. SOX2 represses hepatitis B virus replication by binding to the viral enhii/cp and inhibiting the promoter activation. Viruses. 2020;12(3):273. https://doi.org/10.3390/v12030273