Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma—A Review
Abstract
:1. Introduction
1.1. Hepatocellular Carcinoma
1.2. MicroRNAs
2. The Role of miRNAs in Liver Regeneration
2.1. Cell Proliferation in Hepatocytes
2.2. Apoptosis in Hepatocytes
3. The Role of miRNAs in Liver Diseases Associated with HCC
3.1. Hepatic Lipid Metabolism
3.2. Hepatic Inflammation
3.3. Hepatic Fibrosis
3.4. Hepatitis B Virus
3.5. Hepatitis C Virus
3.6. Alcoholic Liver Disease
3.7. Nonalcoholic Fatty Liver Disease
4. Dysregulation of miRNAs in HCC
4.1. Development of HCC
4.1.1. Oncogenic miRNAs
4.1.2. Tumor Suppressive miRNAs
4.2. miRNAs as Biomarkers for HCC
4.3. miRNAs as Therapeutic Targets for HCC
4.4. miRNAs in HCC Therapy Resistance
5. Conclusions
Author Contributions
Funding
Conflicts of Interest
Abbreviations
HCC | Hepatocellular carcinoma |
miRNA | MicroRNA |
siRNA | Small interfering RNA |
priRNA | PIWI-Interacting RNA |
mRNA | Messenger RNA |
HBV | Viral hepatitis B |
HCV | Viral hepatitis C |
ALD | Alcoholic liver disease |
NAFLD | Nonalcoholic fatty liver disease |
UTR | Untranslated region |
pri-miRNA | Primary microRNA |
DGCR8 | DiGeorge syndrome critical region gene 8 |
TRBP | Transactivation response element RNA-binding protein |
RISC | RNA-Induced silencing complex |
AGO | Argonaute protein |
OncomiR | Oncogenic miRNA |
IL-6 | Interleukin-6 |
TNF-α | Tumor necrosis factor-α |
HGF | Hepatocyte growth factor |
PTEN | Phosphatase and tensin homolog deleted on chromosome |
RhoB | Ras homolog family member B |
PI3K | Phosphoinositide 3-kinase |
mTOR | Mammalian target of rapamycin |
SMAD3 | Small mother against decapentaplegic 3 |
TRAIL | TNF related apoptosis-inducing ligand |
PUMA | P53 upregulated modulator of apoptosis |
STAT3 | Signal transducer and activator of transcription 3 |
TIMP3 | Tissue inhibitor of metalloproteinase 3 |
NASH | Nonalcoholic steatohepatitis |
FASN | Fatty acid synthase |
ACC1 | Acetyl-CoA carboxylase 1 |
IGF | Insulin-like growth factor |
HNF | Hepatocyte nuclear factor |
AMPK | Adenosine 5′-monophosphate-activated protein kinase |
SIRT1 | Sirtuin 1 |
PPAR | Peroxisome proliferator activated receptor |
LXR | Liver X receptor |
SREBP | Sterol regulatory element-binding protein |
HSC | Hepatic stellate cell |
TGF | Transforming growth factor |
ADAM17 | A disintegrin and metalloproteinase 17 |
TLR2 | Toll-Like receptor 2 |
WNT | Wingless-Related integration site |
JAK | Janus kinase |
MAPK | Mitogen-Activated protein kinase |
SOCS3 | Suppressor of cytokine signaling 3 |
HBe | Hepatitis Be |
SHIP1 | SH2-Containg inositol phosphatase 1 |
ULK1 | Unc-51 like autophagy activating kinase 1 |
PCBP | Poly(rC)-Binding protein |
DLC | Deleted in liver cancer |
IRF1 | Interferon regulatory factor 1 |
FN | Fibronectin |
SCD | Stearoyl-CoA desaturase |
CREB1 | cAMP responsive element binding protein 1 |
TRIF | TIR-Domain-Containing adapter-inducing interferon |
HMGA2 | High-Mobility group AT-hook 2 |
C/EBP | CCAAT/enhancer binding protein |
KLF5 | Kruppel-Like factor 5 |
PDK1 | Pyruvate dehydrogenase kinase 1 |
VEGF | Vascular endothelial growth factor |
bFGF | Basic fibroblast growth factor |
MMP2 | Matrix metallopeptidase 2 |
HMGB | High-Mobility group box |
DAMP | Damaged-Associated molecular pattern |
TP53INP1 | Tumor protein p53 inducible nuclear protein 1 |
VFL | von Hippel-Lindau tumor suppressor |
MLH1 | MutL homolog 1 |
CLDN | Claudin |
DDIT | DNA damage-inducible transcript |
IKK | I kappa B kinase |
TAB3 | TGF-beta activated kinase 1 binding protein 3 |
VAV2 | Vav guanine nucleotide exchange factor 2 |
CDC42 | Cell division cycle 42 |
PKB | Protein kinase B |
ROCK | RHO-Associated protein kinase |
EMT | Epithelial-Mesenchymal transition |
PKM2 | Pyruvate kinase M2 |
AFP | α-fetoprotein |
PIVKA-II | Vitamin K absence or antagonists-II |
AMO | AntimiRNA oligonucleotide |
LNA | Locked-Nucleic-Acid antisense oligonucleotide |
MTg-AMO | Antagomirs and multiple-target antimiRNA antisense oligodeoxyribonucleotide |
AAV | Adeno-Associated virus |
TAI | Transcatheter arterial infusion |
ABC | ATP-Binding cassette |
KEAP1 | Kelch-Like ECH-associated protein 1 |
NFE2L2 | Nuclear factor erythroid 2 like 2 |
DUSP6 | Dual specificity phosphatase 6 |
EIF4E | Eukaryotic translation initiation factor 4E |
BRAF | v-Raf murine sarcoma viral oncogene homolog B |
PDGFR3 | Platelet-Derived growth factor receptor 3 |
RASSF1 | Ras association domain family member 1 |
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Liver Disease | miRNA | Function | Reference |
---|---|---|---|
HBV infection | miR-122, miR-99 family | Promote HBV replication | [75,76] |
miR-199-3p, miR-201 | Suppress HBV replication | [77] | |
HCV infection | miR-141 | Promote HCV replication | [78,79] |
let-7 family, miR-21 | Suppress liver fibrosis | [63,80] | |
miR-16, miR-146a, miR-221, miR-222 | Biomarker for liver fibrosis | [81] | |
ALD | let-7 family, miR-19b | Suppress liver fibrosis | [82,83] |
NAFLD/NASH | miR-155 | Promote carcinogenesis | [84,85,86] |
miRNA | Targets | Mechanism | Reference |
---|---|---|---|
miR-10b | CUB and sushi multiple domains 1 (CSMD1) | Division, migration, invasion | [109] |
miR-21 | Kruppel like factors 5 (KLF1), Calmodulin regulated spectrin associated protein family member 1 (CAMSAP1), DEAD-box helicase 1 (DDX1), MARCKS like 1 (MARCKSL1) | Division, cell growth, migration, invasion | [110,111] |
miR-25 | TNF related apoptosis-inducing ligand (TRAIL) | Apoptosis | [112] |
miR-92a | F-box and WD repeat domain containing 7 (FBXW7) | Proliferation, cell cycle transition, apoptosis | [113] |
miR-96-5p | Caspase-9 | Apoptosis | [114] |
miR-107 | High mobility group AT-hock 2 (HMGA2), 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) | Cell growth, Epithelial-mesenchymal transition (EMT) | [115,116] |
miR-135a | Forkhead box O1 (FOX O1) | Migration, invasion | [117] |
miR-155-5p | Phosphatase and tensin homolog (PTEN) | Proliferation, invasion, migration, apoptosis | [118] |
miR-181a | Autophagy related 5 (ATG5) | Autophagy | [119] |
miR-221 | P53, P53 upregulated modulator of apoptosis (PUMA), NF-κB, signal transducer and activator of transcription 3 (STAT3), adeno-associated virus serotype 8 (AAV8), PTEN, metalloproteinase inhibitor 3 (TIMP3), TRAIL | Apoptosis, proliferation | [37,38,39,40,120] |
miR-203a-3p | Interleukin 24(IL-24) | Cell growth, metastasis | [121] |
miR-210 | Fibroblast growth factor receptor like 1 (FGFRL1) | Angiogenesis | [122] |
miR-214-5p | Wiskott-Aldrich syndrome like (WASL) | Invasion, migration | [123] |
miR-302d | Transforming growth factor beta receptor 2 (TGFBR2) | Cell growth, invasion | [124] |
miR-346 | F-box and leucine rich repeat protein 2 (FBXL2) | Proliferation, migration, invasion | [125] |
miR-487a | EVH1 domain containing 2 (SPRED2) 2, phosphoinositide-3-Kinase regulatory 1 (PIK3R1) | Proliferation, metastasis | [126] |
miR-765 | Inositol polyphosphate-4-phosphatase type II B (INPP4B) | Proliferation | [127] |
miR-873 | Tumor suppressor in lung cancer 1 (TSLC1) | Proliferation, migration, invasion | [128] |
miR-892a | CD266 molecule | Proliferation, invasion | [129] |
miR-1249 | Patched 1 (PTCH1) | Cell growth, migration, invasion | [130] |
miR-1468 | Cbp/p300 interacting transactivator with Glu/Asp rich carboxy-terminal domain 2 (CITED2), Up-frameshift protein 1 (UPF1) | Proliferation, apoptosis | [131] |
miR-3910 | Macrophage stimulating 1 (MST1) | Cell growth, migration | [132] |
miR-4417 | Tripartite motif containing 35 (TRIM35), pyruvate kinase muscle 2 (PKM2) | Proliferation, apoptosis | [133] |
miRNA | Targets | Mechanism | Reference |
---|---|---|---|
miR-15b | B cell CLL/lymphoma 2 (BCL2) | Proliferation, apoptosis | [35] |
miR-26 | unc-51 like autophagy activating kinase 1 (ULK1) | Autophagy | [134] |
miR-29a | Claudin 1 (CLDN1) | Cell growth, migration | [135] |
miR-31-5p | Sp1 transcription factor (SP1) | Proliferation, migration, invasion | [136] |
miR-33b | Spalt-like transcription factor 4 (SALL4) | Proliferation, metastasis | [137] |
miR-98 | Enhancer of zeste homolog 2 (EZH2) | Proliferation | [138] |
miR-122 | A disintegrin and metalloproteinase domain 10 (ADAM10), ADAM17, insulin like growth factor 1 receptor (IGF1R), Serum response factor (SRF), Cyclin G1, Snail family transcriptional repressor 1 (SNAl1), SNAl2 | Proliferation, invasion, EMT | [41,139] |
miR-125a-5p | Sirtuin 7 (SIRT7), erb-b2 receptor tyrosine kinase 3 (ERBB3) | Proliferation, apoptosis | [140,141] |
miR-125b | Myeloid cell leukemia 1 (MCL1), BCLw, IL-6R, SIRT7 | Apoptosis, proliferation | [35,141] |
miR-126 | Vascular endothelial growth factor (VEGF) | Angiogenesis | [142] |
miR-137 | EZH2 | Proliferation | [143] |
miR-142 | Transforming growth factor β (TGFβ), Thrombospondin 4 (THBS4) | Cell growth, metastasis, migration, invasion | [144,145] |
miR-142-3p | Lactate dehydrogenase A (LDHA) | Proliferation | [146] |
miR-144 | Zinc finger protein X-linked (ZFX) | Proliferation, invasion, migration | [147] |
miR-187-3p | S100 calcium binding protein A4 (S100A4) | Metastasis, EMT | [148] |
miR-194 | Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) | Proliferation | [149] |
miR-195 | Cyclin D1/3, cyclin-dependent kinase 4/6 (CDK4/6), Cell division cycle 42 (CDC42), Vav guanine nucleotide exchange factor 2 (VAV2), E2F2, BCL2, BCLw, VEGF | Proliferation, apoptosis, angiogenesis, metastasis | [150,151] |
miR-199a-3p | VEGFA, VEGFR1-2, Matrix metallopeptidase 2 (MMP2), Hepatocyte growth factor (HGF), Yes 1 associated transcriptional regulator 1 (YAP1) | Angiogenesis, proliferation, apoptosis | [152,153] |
miR-199b-5p | TGFβ | EMT | [154] |
miR-200a | GRB2 associated binding protein 1 (GAB1) | Invasion, migration | [155] |
miR-203 | IL1β, SNAl1, Twist family bHLH transcription factor 1 (TWIST1) | Proliferation, metasis | [156] |
miR-206 | Cyclin D1, CDK6 | Proliferation | [157] |
miR-212 | FOXM1 | Migration, cell growth | [158] |
miR-296 | Fibroblast growth factor receptor 1 (FGFR1) | proliferation, apoptosis | [159] |
miR-302b | Epidermal growth factor receptor (EGFR), AKT serine/threonine kinase 2 (AKT2) | proliferation, invasion, metastasis | [160,161] |
miR-337 | HMGA3 | Proliferation, apoptosis | [162] |
miR-338-3p | Metastasis associated in colon cancer 1 (MACC1), β-catenin, VEGF | Angiogenesis | [163] |
miR-340 | Janus kinase 1 (JAK1) | Proliferation, invasion | [164] |
miR-345 | Interferon regulatory factor 1 (INF1) | Metastasis, EMT | [165] |
miR-370 | Pim-1 proto-oncogene, serine/threonine kinase (PIM1) | Cell growth, invasion | [166] |
miR-451 | IL6R | Angiogenesis | [167] |
miR-497 | RPTOR independent companion of MTOR (RICTOR) | proliferation, migration and invasion | [168] |
miR-495 | IGF1R | Proliferation, invasion | [169] |
miR-539 | Fascin actin-bundling protein 1 (FSCN1) | Migration, invasion | [170] |
miR-638 | SRY-box transcription factor 2 (SOX2), VEGF | Invasion, EMT, angiogenesis | [171,172] |
miR-663a | HMGA2 | Proliferation, invasion | [173] |
miR-874 | δ opioid receptor (DOR) | Proliferation, metastasis | [174] |
miR-940 | C-X-C motif chemokine receptor 2 (CXCR2) | Migration, invasion | [175] |
miR-1271-5p | FOXK2 | Cell growth | [176] |
miR-1299 | CDK6 | Proliferation | [177] |
miR-1301 | BCL9, β-catenin, VEGFA | Migration, invasion, angiogenesis | [178] |
miRNA | Expression | Background | Reference | |
---|---|---|---|---|
Diagnosis | let-7 | up | HBV infection | [202] |
miR-101 | down | HBV infection | [203] | |
miR-122 | up | HBV infection, HCV infection | [202,205] | |
miR-125a-5p | up | HBV infection, HCV infection | [204] | |
miR-223-3p | down | HBV infection | [204] | |
Poor prognosis | miR-32-5p | up | HBV infection and others | [208] |
miR-33a | down | Unknown | [207] | |
miR-92a | up | HBV infection and others | [113] | |
miR-122 | up | HBV infection, HCV infection | [210] | |
miR-137 | down | HBV infection and others | [143] | |
miR-148a | up | HBV infection, HCV infection | [210] | |
miR-194 | down | Unknown | [149] | |
miR-221 | up | HBV infection and others | [206] | |
miR-296 | down | HBV infection and others | [159] | |
miR-487a | up | HBV infection and others | [126] | |
miR-638 | down | HBV infection, HCV infection and others | [209] | |
miR-940 | down | HBV infection and others | [175] | |
miR-1246 | up | HBV infection, HCV infection | [210] | |
miR-1468 | up | HBV infection and others | [131] |
Drug | miRNA | Target | Reference |
---|---|---|---|
Cisplatin | miR-33a-5p | SOCS3 | [220,221] |
miR-363 | MCL1 | [223] | |
Doxorubicin | miR-133a | ABC subfamily C1 | [224] |
miR-326 | ABC subfamily C1 | [224] | |
5-FU | miR-141 | Kelch-like ECH-associated protein 1 (KEAP1), Nuclear factor erythroid 2 like 2 (NFE2L2) | [225] |
miR-125b | BCL2 | [14] | |
miR-195 | BCL2 | [14] | |
miR-503 | eukaryotic translation initiation factor 4E (EIF4E) | [228] | |
Sorafenib | miR-93 | p21Cip/Waf1 | [222] |
miR-181 | Ras association domain family 1 (RASSF1) | [230] | |
miR-216a | p21Cip/Waf1 | [222] | |
miR-217 | p21Cip/Waf1 | [222] | |
miR-494 | PTEN, mTOR | [231] |
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Oura, K.; Morishita, A.; Masaki, T. Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma—A Review. Int. J. Mol. Sci. 2020, 21, 8362. https://doi.org/10.3390/ijms21218362
Oura K, Morishita A, Masaki T. Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma—A Review. International Journal of Molecular Sciences. 2020; 21(21):8362. https://doi.org/10.3390/ijms21218362
Chicago/Turabian StyleOura, Kyoko, Asahiro Morishita, and Tsutomu Masaki. 2020. "Molecular and Functional Roles of MicroRNAs in the Progression of Hepatocellular Carcinoma—A Review" International Journal of Molecular Sciences 21, no. 21: 8362. https://doi.org/10.3390/ijms21218362