Table 1.
HBx-dysregulated epi-miRNA and their targets in HBV-HCC.
| HBx-epi-regulator | miRNA | Epi target | HBV-HCC gene target | Immune gene target | Epi-Ref | HCC Reference |
|---|---|---|---|---|---|---|
| HMT/EZH2 LIN28/tet1/EED/SUZ12 | Let-7c | SUZ12/EED/EZH1/2 | CNKD1/PRICKLE/SFRP5/B-CAT/STAT3/RAS/HMGA2/MYC/ IL-6/IL-10/TLR-4/COL1A2/NGF/BCL-XL/BCL-2/MCL-1z | MYC/STAT3/IFN-b/RAS/TLR4 BCL-XL/SMAD2/SMAD4/NFZ APC2/WNT1/HMGA2/PLZF/IFN/IL-4/IL-17/LIN28B/IGF2BP1 | (13–15) | (16–19) |
| DNMT | miR-1 | HDAC4 | EDN1/PI3K/AKT/METFOXP1 | E2F5/HSP60/HSP70/KCNJ2/GJA1 | (20–22) | (20, 21, 23) |
| HMT/EZH2/EED/C-MYC/SUZ12 | miR-101 | DNMT3A/EZH2/EED/SUZ12/ | GSTP1/FOS/MCL-1/RASSF1A/PRDM2/CNKD1/PRICKLE/SFRP5/B-CAT/AP1/DUSP1/MCL-1/ROCK2/ATG4D/MTOR/SOX9/COX2/RAB5A/STMN1/DNMT3A/FOS/RAP1B/VEGF | ICOS (naïve T-cells)/MCL-1 | (13, 14, 24) | (25) (14, 24, 26–28) |
| DNMT/PPARα | miR-122 | CTNNB1/CCNG1 modulated p53/GLD2/NDRG3/GALNT10/CCNG1/PTTG1/PBF/ADAM10/CCNG1/Igf1R/ADAM 17/BCL-W/NDRG3 | SOCS3/IFN/IP-10/BCL-W | (29, 30) | (31–34) | |
| DNMT1 | miR-124 | EZH2/BMI1 | STAT3/PIK3CA/ROCK2/STAT3/Cyclin D/CDK6, VIM, SMYD3, E2F6, IQGAP1 | STAT3/TRAF6/CYCLIND3/BM11 | (14, 35, 36) | (37) |
| miR-125a | SIRT7 | MMP11/VEGF-A/ERBB2/HBsAg | NF-α/BCL-2/KLF13/BMF | (38, 39) | (40–42) | |
| EZH1/2/HMT/SUZI2/EED/p53 | miR-125b | SIRT7/SUZI2 SUV39H1/EED/EZH1/EZH2/ | SMAD2/4/Sirtuin7/SUV39H1/LIN28 B/PIGF/BCL-2/MCL-1/CNKD1/PRICKLE/SRFRP5/B-CAT/PIGF/MMP2/MMP9 | PRDM1/IRF4/TNF_/BCL-2/MCL-1/LIN28/IRF4/KLF13/BMF/BCL-2/SMAD2/SMAD4 APC2/WNT1//KLF13/TRP5 3INPI/LIN28A/IRF4/BLIMP1 IRF4/BMF | (13, 36, 43, 44) | (45, 46) |
| DNMT3 | miR-132 | p300 | AKT/GSK3/WNT-BCAT | p300/IRAK4/FOXO3/SOX4/ | (47, 48) | (48) |
| HMT/EED/SUZ12/EZH2 | miR-139-5p | EED/SUZ12/EZH1/2 | ZEB1/2/CNKD1/PRICKLE/SFRP5/B-CAT | IL-4/IFN-γ | (13, 14) | (45, 49, 50) |
| miR-140 | DNMT1 | NF-kB/TGFβRI/FIF9/Pin1 | (51) | |||
| miR-145 | HDAC2 | MAP3K/CUL5/ADAM17 | IFN-b/TIRAP/TRAF6 | (52–54) | (55–57) | |
| DNMT1/p53C-MYC | miR-148a | DNMT1 | HPIP/AKT/ERK/FOXO4/ATF5/ERBB3/BCL-2/IRS-1/MTOR/MET/ACVR1/SNAIL/IGF-IR/MIG6/CAND1/CDC25B | CaMKIIα/KIT/MET/SIPI/BACH/PTEN/BIM/GADD45 | (58, 59) | (45, 60–62) |
| miR-152 | DNMT1/DNMT3A | GSTP/CDH1/KIT | CaMKII/KIT | (22, 47, 63) | (42, 63–65) | |
| HDAC-I/EZH2 | miR-155 | PRC2/Phf19/p300/CBP | PTEN/SOX6/ZHX2/SOCS1 | AID/Blimp-1/PRDM1/IFN/SHIP1/SOCSI/BMAL1/PU.1/BACH1/CSFIR/CEBP/ETS1/Th2 induction3/SOCS1/C/EBP/AID/FOXP3 | (43, 66, 67) | (66, 68, 69) |
| HDAC-I SAHA/ C-MYC | miR-17-92 family | DNMT | E2F1, Cyclin G1/PTEN/p21/p27/p57/cccDNA | TNFSF9/CCL-5/IKBKE/c-MAF/AMLI/TP53INPI c-MAF/IFN/CD69/PTEN/TGFBR11/p27/p21/E2F/PHLPP2/BIM/CREB1 | (70, 71) | (72–74) |
| HMT | miR-199a/b | CHC | CD19+ | (75) | (76) | |
| DNMT/p53 | miR-200a | HDAC4 | ZEB1/2/HNF-3β Rho/ROCK/ASB4 | (77, 78) | (45, 79) | |
| EED/SUZ12/EZH1/2 | miR-200b | EED/SUZ12/EZH1/2 | CNKD1/PRICKLE/SFRP5/B-CAT | (13, 78) | (45, 79) | |
| EZH2/BMI1 | miR-203 | RAP1A | SMAD1/BCL11B/RARB/PRKCA/PRKCB1/FMRP | (80) | (81) | |
| DNMT | miR-205 | ACSL4/E2F1/ZEB1/2 | (82) | (45, 82, 83) | ||
| DNMT | miR-221 | HDAC6 | ERα/DDIT4/BMF/p27 p57/PTEN/p21/SOCS3 | PTEN/SOCS3/p57/KIT/p27 | (84, 85) | (86–88) |
| DNMT | Mir-222 | P27kip 1/PTEN/PPP2R2A/p57/p21 | p27 kip 1/PTEN/KIT | (85) | (55, 88–90) | |
| HAT/HDAC1/3/EP300/p50/p65 | miR-224 | PAK4/MMP9 inhibitor-5/SMAD4 | AP15/SMAD4 | (91, 92) | (93–95) | |
| miR-26a | EZH2 | IL-6/IFN_/ER_/Cyclin D2/Cyclin E2/c-JUN/CDK4/6 | IFN-b CDK4/6/MALT1 | (96–98) | (99–101) | |
| miR-29c | DNMT3B/SIRT1 | BCL-2/MCL-1/TNFA1P3 | TCL-1/MCL-1/IFN- | (102–104) | (105, 106) | |
| H3K4ac | miR-29a/b | DNMT1/DNMT3A/B/SETDB1/H3K9/SIRT1 | PTEN/PI3K/AKT/MMP-2 | IFNARI/IFN/T-Bet/EOMES/PTEN/MCL-1/IFN-/SLFN4/CDC42/HBP1/TCL1 | (22, 102, 103, 107, 108) | (55, 109) |
| HBx/P53/DNMT1/3A/3B | miR-34a | SIRTI | CCL22/MAP4K4/SIRT1/CCND1/CDK4/6/MET/C-JUN/CDK2 | IFN-b/FOXP1/CDK2/4/6/CCL22/FOXPN | (110) | (111–115) |
| HDAC | miR-373 | HDAC/SIRT1 | SNAIL-1/CDH1 | MTOR/SIRT1/RELA | (116) | (116) |
| miR-548a | HDAC4 | HBXIP, IFN-λ1 | IFN-λ1 | (117) | (118, 119) |
Column 1 indicates upstream epigenetic proteins that can influence miRNA expression in column 2 (blue miRNA- downregulated and red miRNA-upregulated). Column 3 is downstream epigenetic targets of dysregulated miRNA. Columns 4 and 5 are specific HBV-HCC and immune gene targets. Column 6 refers to epigenetic references only (column 1 and 3) and column 7 to HBV-HCC and immune gene targets.