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

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.

Hepatitis B Viral Protein HBx and the Molecular Mechanisms Modulating the Hallmarks of Hepatocellular Carcinoma: A Comprehensive Review

“…Attenuation of the antiviral immune response can also be accomplished by HBx-mediated epigenetic modulation and miRNA dysregulation [ 133 ]. HBx-dysregulated tumour suppressor miR-101 reduces LPS-stimulated macrophage expression, capable of inducing HCC, due to its inability to modulate DUSP1 phosphatase enzyme, which leads to impaired ERK1/2/p38/JNK elevation of pro-inflammatory cytokines such as TGF-β [ 134 ].…”

“…HBx-dysregulated tumour suppressor miR-101 reduces LPS-stimulated macrophage expression, capable of inducing HCC, due to its inability to modulate DUSP1 phosphatase enzyme, which leads to impaired ERK1/2/p38/JNK elevation of pro-inflammatory cytokines such as TGF-β [ 134 ]. To gain a more comprehensive insight into HBx influence on a plethora of miRNA dysregulation pathways and their associated immune response, refer to Sartorius et al [ 133 ].…”

Role of Virus-Induced Host Cell Epigenetic Changes in Cancer

“…Several studies showed a role for HBx in up- and downregulating the expression of cellular microRNAs, including miR-10, miR-132, miR-143, and miR-193b. This has been the topic of excellent reviews [ 190 , 255 , 257 , 263 , 291 , 292 ]. HBx modulates microRNA expression by inducing epigenetic changes in microRNA-encoding genes or modulating expression of genes whose products are involved in microRNA biogenesis.…”

“…Moreover, HBx can repress Drosha expression leading to dysregulation of microRNA biogenesis [ 298 ]. MicroRNAs modulated by HBx were demonstrated to target genes that encode proteins involved in cell cycle progression, cell survival, immune evasion, invasiveness and migration, and angiogenesis [ 292 ]. Thus, dysregulation of microRNA expression is a pivotal mechanism by which HBV promotes hepatocellular carcinogenesis.…”

HBx increases chromatin accessibility and ETV4 expression to regulate dishevelled-2 and promote HCC progression

“…An early study showed that altered host gene expression by HBx caused the occurrence of HCC in transgenic mice [ 13 ]. The HBx protein regulates its target genes through epigenetic modification in the pathogenesis of HBV–HCC [ 14 ]. In a previous study, we confirmed that activation of key oncogenes by epigenetic modification is a key factor leading to the occurrence and development of HBV-related HCC [ 15 ].…”