The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation - PubMed (original) (raw)

Review

The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation

Kurt Sartorius et al. Front Immunol. 2021.

Abstract

Hepatitis B virus (HBV)-associated hepatocellular carcinoma (HBV-HCC) pathogenesis is fueled by persistent HBV infection that stealthily maintains a delicate balance between viral replication and evasion of the host immune system. HBV is remarkably adept at using a combination of both its own, as well as host machinery to ensure its own replication and survival. A key tool in its arsenal, is the HBx protein which can manipulate the epigenetic landscape to decrease its own viral load and enhance persistence, as well as manage host genome epigenetic responses to the presence of viral infection. The HBx protein can initiate epigenetic modifications to dysregulate miRNA expression which, in turn, can regulate downstream epigenetic changes in HBV-HCC pathogenesis. We attempt to link the HBx and miRNA induced epigenetic modulations that influence both the HBV and host genome expression in HBV-HCC pathogenesis. In particular, the review investigates the interplay between CHB infection, the silencing role of miRNA, epigenetic change, immune system expression and HBV-HCC pathogenesis. The review demonstrates exactly how HBx-dysregulated miRNA in HBV-HCC pathogenesis influence and are influenced by epigenetic changes to modulate both viral and host genome expression. In particular, the review identifies a specific subset of HBx induced epigenetic miRNA pathways in HBV-HCC pathogenesis demonstrating the complex interplay between HBV infection, epigenetic change, disease and immune response. The wide-ranging influence of epigenetic change and miRNA modulation offers considerable potential as a therapeutic option in HBV-HCC.

Keywords: HBx; epigenetic modulation; hepatitis B virus-associated hepatocellular carcinoma; immunology; microRNA.

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Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1

HBx induced epigenetic expression in HBV-HCC. (A) HBx recruits the CUL4/DDB1 ubiquitination complex to repress SMC5/6 and promote DNA relaxation and cccDNA transcription. (B) HBx recruits CBP/p300 (pCAF) to transactivate HAT (H3K9ac) to promote cccDNA expression. (C) HBx promotes DNMT to repress SOCS1/RASSF1A tumor suppressors that fail to modulate HCC pathogenesis. (D) HBx promotes PLK1 to block HMTs (EZH1/2/EED/SUZ12) that then fail to modulate B-CATENIN induced hepatocarcinogenesis. (E) HBx initiates HMTs (SMYD3) to promote C-MYC induced HCC. (F) HBx promotes HDAC to silence cell cycle controls like p21/p26 and promote HCC.

Figure 2

Epi-miR-101 in HBV-HCC and immune pathways. HDAC-Histone deacetylation, HAT-histone acetylation, HMT-Histone methylation, DNMT-DNA methylation (pathways in dark red involve identified direct upstream or downstream epigenetic proteins/enzymes). HBx protein can downregulate or initiate HDAC/HAT/DNMT/HMT to repress miR-101 modulation in various HBV-HCC pathways including WNT-B-CATENIN, TP53, and P13K/AKT to influence HCC pathogenesis. HBx epigenetically downregulated miR-101 also regulates macrophage and DC expression in the innate immune system, as well as T-cell and B-cell expression in the adaptive immune system.

Figure 3

Epi-miR-29 in HBV-HCC and immune pathways. HDAC-Histone deacetylation, HAT-histone acetylation, DNMT-DNA methylation, PRC1/2- Polycomb Repressive Complex, SETDB1-SET Domain Bifurcated Histone Lysine Methyltransferase, TET1-Ten-eleven translocation methylcytosine dioxygenase 1 (pathways in dark red involve identified direct upstream or downstream epigenetic proteins/enzymes). HBx protein can downregulate or initiate HDAC/HAT/DNMT/HMT to upregulate miR-29 modulation in various HBV-HCC pathways including AKT/MTOR, TP53, and JAK/STAT to influence HCC pathogenesis. HBx epigenetically upregulated miR-29 also regulates macrophage and DC/NK expression in the innate immune system, as well as T-cell and B-cell expression in the adaptive immune system.

Figure 4

Epi-miR-148/152 in HBV-HCC and immune pathways. HDAC-Histone deacetylation, HAT-histone acetylation, DNMT-DNA methylation, HMT-Histone methylation (pathways in dark red involve identified direct upstream or downstream epigenetic proteins/enzymes). HBx protein can downregulate or initiate HDAC/HAT/DNMT/HMT to repress miR-148/152 modulation in various HBV-HCC pathways including WNT-B-CATENIN, TP53, and AKT/mTOR to influence HCC pathogenesis. HBx epigenetically downregulated miR-148/152 also regulates DC expression in the innate immune system, as well as T-cell and B-cell expression in the adaptive immune system.

Figure 5

Epi-miR-155 and HBV-HCC and immune pathways. HDAC-Histone deacetylation, HAT-histone acetylation, DNMT-DNA methylation, PRC1/2- Polycomb Repressive Complex 1 and 2 (pathways in dark red involve identified direct upstream or downstream epigenetic proteins/enzymes). HMT-Histone methylation. HBx protein can downregulate or initiate HDAC/HAT/DNMT/HMT to upregulate miR-155 modulation in various HBV-HCC pathways including AKT/MTOR, TP53, and JAK/STAT to influence HCC pathogenesis. HBx epigenetically upregulated miR-155 also regulates germinal matrix (GM) population and NF-kB expression in the innate immune system, as well as T-cell and B-cell expression in the adaptive immune system.

References

1. Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global Cancer Statistics 2018: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J Clin (2018) 68(6):394–424. 10.3322/caac.21492 - DOI - PubMed
1. Ginzberg D, Wong RJ, Gish R. Global HBV burden: guesstimates and facts. Hepatol Int (2018) 12(4):315–29. 10.1007/s12072-018-9884-8 - DOI - PubMed
1. Yang JD, Hainaut P, Gores GJ, Amadou A, Plymoth A, Roberts LR. A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol (2019) 16(10):589–604. 10.1038/s41575-019-0186-y - DOI - PMC - PubMed
1. Dandri M, ed. Epigenetic modulation in chronic hepatitis B virus infection. Seminars in Immunopathology. Springer Berlin Heidelberg: Springer; (2020). 10.1007/s00281-020-00780-6 - DOI - PMC - PubMed
1. Koumbi L, Karayiannis P. The epigenetic control of hepatitis B virus modulates the outcome of infection. Front Microbiol (2016) 6:1491. 10.3389/fmicb.2015.01491 - DOI - PMC - PubMed

The Epigenetic Modulation of Cancer and Immune Pathways in Hepatitis B Virus-Associated Hepatocellular Carcinoma: The Influence of HBx and miRNA Dysregulation - PubMed (original) (raw)