The Multiple Roles of Hepatitis B Virus X Protein (HBx) Dysregulated MicroRNA in Hepatitis B Virus-Associated Hepatocellular Carcinoma (HBV-HCC) and Immune Pathways

Abstract

Currently, the treatment of hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) [HBV-HCC] relies on blunt tools that are unable to offer effective therapy for later stage pathogenesis. The potential of miRNA to treat HBV-HCC offer a more targeted approach to managing this lethal carcinoma; however, the complexity of miRNA as an ancillary regulator of the immune system remains poorly understood. This review examines the overlapping roles of HBx-dysregulated miRNA in HBV-HCC and immune pathways and seeks to demonstrate that specific miRNA response in immune cells is not independent of their expression in hepatocytes. This interplay between the two pathways may provide us with the possibility of using candidate miRNA to manipulate this interaction as a potential therapeutic option.

Keywords: HBx protein; dysregulated; hepatitis B virus; hepatocellular carcinoma; microRNA.

Figure 1

HBx induced MiR-155 in HBV-HCC immune pathways: This HBx-upregulated onco-miRNA promotes MTOR signaling and EMT in the P13K/MAPK pathway; it promotes β-Catenin expression to promote oncogenic proteins like C-MYC in the WNT/β-Catenin pathway; it subdues SOCSI suppression of JAK/STAT signaling to promote oncogenic proteins like C-MYC and CCND1 in the JAK/STAT pathway and it reduces expression of tumor suppressors like p21/waf1/cip 1 to promote cell proliferation in the TP53 pathways. This upregulated miRNA, however, reduces HBV replication by repressing C/EBP promotion of ENH11/core promoter. In the immune pathway, this miRNA influences granulocyte/monocyte populations via repressing SHIP1; it represses SHIP1/SOCS1 to promote NF-κB/TLR induction of macrophages; in DCs this miRNA represses PU.1 induction of DC-SIGN to reduce pathogen cell surface uptake; in T-cell synthesis this miRNA can repress SOCS1 to promote Treg production, it can promote Th1:Th2 ratio by repressing C-MAF; in B-cells this miRNA represses PU.1 to promote GC differentiation into memory or plasma cells.

Figure 2

HBx-upregulated MiR-17-92 family in HBV-HCC immune pathways: This HBx-dysregulated miRNA family (via C-MYC) promotes HBV-HCC progression in the P13K/MAPK by repressing PTEN to upregulate MTOR signaling; in the TP53 pathways it can increase cell proliferation by repressing p21/p27/p57 and E2F1 cell cycle control primarily by promoting MTOR signaling and blocking cell cycle controls. Upregulated family can also repress HBV replication. In monopoiesis, upregulated family members can increase macrophage development via repressing RUNX1 to promote CSFR stimulation; in T-cells upregulated family members can repress PTEN/BIM to increase Th1 versus Treg expression; conversely it can repress CD69 to modulate T-cell output; B-cell output is increased when upregulated family members repress PHLPP2 to promote ICOS/P1(3)K stimulation of T_FH induced B-cell response.

Figure 3

HBx-induced mIR-181a in HBV-HCC immune pathways: This HBx-upregulated miRNA promotes cell proliferation in the TP53 pathway by repressing cell cycle controls like E2F5 and it exerts an anti-apoptotic influence by repressing FAS/ATG5 to promote cell survival; in the P13K/MAPK this upregulated miRNA also promotes carcinogenesis by promoting MTOR signaling as a result of repressing PTEN. In the innate immune pathways, this miRNA promotes an anti-inflammotory response by repressing Ilα and C-FOS/IL-6/TNFα in monocytes and DCs respectively; in NKs this miRNA upregulates NKs by repressing NLK, which then fails to repress NOTCH induced induction of NKs; in T-cells this miRNA represses DUSP5/6/SHP2/PTPN22 to increase TCR signaling induced stimulation of T-cells; however, this upregulated miRNA also represses T-cell production by reducing CD69 expression; in early stage leukopiesis this miRNA can also promote B-cell to T-cell differentiation in favor of B-cells by repressing DUSP5/6/SHP2/PTPN22.

Figure 4

HBx-induced MiR-21 in HBV-HCC immune pathways: In the P13K/MAPK pathway this HBx-upregulated miRNA also promotes HCC by upregulating mTOR signaling via repressing PTEN; in the WNT/β-Catenin pathway, it promotes the onco-protein β-Catenin by regulating a suppressor of WNT signaling, as well as by repressing CADHEREN via reducing PDCD4 modulation of SNAIL which acts as a repressor of CADHEREN. In macrophages, this upregulated miRNA exerts a pro and anti-inflammatory influence by repressing PDCD4. In the first case, the repression of PDCD4 reduces its own repressive of pro-inflammatory NF-κB led signaling, in the second case the repression of PDCD4 stimulates the upregulation of the anti-inflammatory IL-10; this upregulated miRNA can increase DC output by repressing JAG1; in T-cells, this miRNA can promote Th17 expression by suppressing SMAD7, which is a negative regulator of TGFβ, as well as reduce Th1:Th2 ratio by targeting IL-12 induction of INFs to promote Th1.