HCC-Related lncRNAs: Roles and Mechanisms
Abstract
:1. Introduction
2. Epigenetic Regulation
2.1. DNA Methylation: Beyond the Methyl Mark
2.2. Histone Modifications: The Chromatin Code
2.3. Noncoding RNAs: Epigenetic Mediators
3. Introduction to lncRNAs: Mechanisms and Modes of Action
3.1. Gene Expression Regulation
3.1.1. Regulation of Chromatin
LncRNA–Protein Interaction Mediating Chromatin Regulation
LncRNA-DNA Interaction Mediating Chromatin Regulation
3.1.2. Regulation of Transcription
3.2. Post-Transcriptional Regulation
3.3. Liquid–Liquid Phase Separation (LLPS)
3.4. lncRNAs Coding Micropeptides
4. Significance of Studying lncRNAs in HCC
5. LncRNAs in NASH and Viral Hepatitis, Risk Factors Contributing to HCC
5.1. NASH
5.2. Viral Hepatitis
6. LncRNAs Regulating HCC
6.1. LncRNAs Functioning as Oncogenes
6.1.1. HOTAIR
6.1.2. MALAT1
6.1.3. HULC
6.1.4. PVT1
6.1.5. HOTTIP
6.1.6. H19
6.1.7. NEAT1
6.1.8. HEIH
6.1.9. SNHG6
6.1.10. Additional lncRNAs Functioning as Oncogenes
LncRNAs Modulating Wnt/β-Catenin Signaling
LncRNAs Promoting HCC by Regulating Metabolism
lncRNAs Regulating EMT and Metastasis
lncRNAs Regulating Vascular Invasion
lncRNAs Regulating Oncogenic AKT Pathway
Miscellaneous Functions of lncRNAs in HCC
6.2. lncRNAs Functioning as Tumor-Suppressor Genes
6.2.1. MEG3
6.2.2. GAS5
6.2.3. FENDRR
6.2.4. Additional lncRNAs Functioning as Tumor Suppressors
7. lncRNAs Modulating Current HCC Treatment
8. Conclusions and Future Perspectives
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
53BP1 | p53 binding protein 1 |
AAV | Adeno-associated virus |
ABCG2 | ATP binding cassette subfamily G member 2 |
ACSL1 | Acyl-CoA synthetase long-chain family member 1 |
AEG-1 | Astrocyte elevated gene-1 |
AFP | Alpha-fetoprotein |
AKR1C2 | Aldo-keto reductase family 1 member C2 |
AKT | Akt kinase |
ALS | Amyotrophic lateral sclerosis |
AMPKβ2 | Adenosine monophosphate-activated protein kinase subunit beta 2 |
ANRIL/CDKN2B-AS1 | Antisense noncoding RNA in the INK4 locus/CDKN2B antisense RNA 1 |
ANXA8 | Annexin A8 |
APC | APC regulator of WNT signaling pathway |
ASO | Antisense oligonucleotide |
ASRPS | A small regulatory peptide of STAT3 |
ASS1 | Arginosuccinate synthase 1 |
ATG3 | Autophagy related 3 |
ATG14 | Autophagy related 14 |
ATP | Adenosine triphosphate |
BBOX1-AS1 | BBOX1 antisense RNA 1 |
BMI1 | BMI1 proto-oncogene, polycomb ring finer |
B-NSG | NOD-Prkdcscid Il2rgtm1/Bcgen |
BRD3 | Bromodomain containing 3 |
CAPRIN1 | Cell cycle associated protein 1 |
CASC9 | Cancer susceptibility 9 |
CBX7 | Chromobox 7 |
CCT3 | Chaperonin containing TCP1 subunit 3 |
CDIPTOSP | CDIP transferase opposite strand, pseudogene |
CDKN2A | Cyclin-dependent kinase inhibitor 2A (p16) |
CDKN2B | Cyclin-dependent kinase inhibitor 2B (p15) |
CELF1 | CUGBP Elav-like family member 1 |
ceRNA | Competitive endogenous RNA |
CHASERR | CHD2 adjacent suppressive regulatory RNA |
CHD2 | Chromodomain helicase DNA binding protein 2 |
CIP2A-BP | CIP2A binding peptide |
CLOCK | Clock circadian regulator |
COX2 | Cytochrome c oxidase subunit II |
CREB | cAMP-response element binding protein |
CSC | Cancer stem cells |
CT | Computed tomography |
ctDNA | Circulating tumor deoxyribonucleic acid |
CRISPR | Clustered regularly interspaced short palindromic repeats |
CTNNB1 | Catenin beta 1 (β-catenin) |
CUL4A | Cullin 4A |
CYTB | Cytochrome b |
DANCR | Differentiation antagonizing non-protein coding RNA |
DDR | DNA damage response |
DDX5 | DEAD-box helicase 5 |
DDX17 | DEAD-box RNA helicase 17 |
DDX21 | DExD-box helicase 21 |
DEN | Diethylnitrosamine |
DFC | Dense fibrillar component |
DIGIT | Divergent to GSC, induced by TGF-β family signaling |
DILC | Downregulated in liver cancer stem cells |
dilncRNA | Damage-induced lncRNA |
DNA | Deoxyribonucleic acid |
DNMT1 | DNA methyltransferase 1 |
DNMT2 | DNA methyltransferase 2 |
DPP4 | Dipeptidyl peptidase 4 |
DSB | Double-strand break repair |
E2F1 | E2F transcription factor 1 |
EEF1E1 | Eukaryotic translation elongation factor 1 epsilon 1 |
EGFR | Epidermal growth factor receptor |
EMT | Epithelial-mesenchymal transition |
EPCAM | Epithelial cell adhesion molecule |
ER | Endoplasmic reticulum |
ESC | Embryonic stem cells |
EV | Extracellular vesicle |
EZH2 | Enhancer of zeste 2 polycomb repressive complex 2 subunit |
FAF2 | Fas associated factor family member 2 |
FC | Fibrillar center |
FDA | Food and drug administration |
FENDRR | FOXF1 adjacent noncoding developmental regulatory RNA |
FOXC1 | Forkhead box C1 |
FOXM1 | Forkhead box M1 |
FUS | FUS RNA-binding protein |
GADD45A | Growth arrest and DNA damage-inducible alpha |
GADD45B | Growth arrest and DNA damage-inducible beta |
GAS5 | Growth arrest specific 5 |
GIRGL | glutamine insufficiency regulator of glutaminase lncRNA |
GLS1 | Glutaminase 1 |
GPC3 | Glypican-3 |
GR | Glucocorticoid receptor |
GRP78 | Glucose regulated protein 78 |
H19 | H19 imprinted maternally expressed transcript |
H3K4me3 | Trimethylation of histone H3 at lysine 4 |
H3K27me3 | Trimethylation of histone H3 at lysine 27 |
H3K9ac | Acetylation of histone H3 at lysine 9 |
H3K18ac | Acetylation of histone H3 at lysine 18 |
H3K56ac | Acetylation of histone H3 at lysine 56 |
HAND2-AS1 | HAND2 antisense RNA 1 |
HBV | Hepatitis B virus |
HCC | Hepatocellular carcinoma |
HCV | Hepatitis C virus |
HEIH | Hepatocellular carcinoma upregulated EZH2-associated long noncoding RNA |
HIF1A | Hypoxia-inducible factor 1 subunit alpha |
HIG2 | Hypoxia-inducible protein 2 |
HK2 | Hexokinase 2 |
HMGA2 | High mobility group AT-hook 2 |
HNRNPK | Heterogenous nuclear ribonucleoprotein K |
HNRNPL | Heterogenous nuclear ribonucleoprotein L |
HNRNPU | Heterogenous nuclear ribonucleoprotein U |
HOTAIR | HOX transcript antisense RNA |
HOTTIP | HOXA distal transcript antisense RNA |
HSP90 | Heat shock protein 90 |
HULC | Highly upregulated in liver cancer |
HuR | Human antigen R |
ICAM1 | Intercellular adhesion molecule 1 |
ICR | ICAM-1-related |
IDR | Intrinsically disordered region |
IGF2 | Insulin-like growth factor 2 |
IL-6 | Interleukin 6 |
IL-11 | Interleukin 11 |
JAK | Janus kinase |
KLF2 | KLF transcription factor 2 |
KMT2A/MLL | Lysine methyltransferase 2A |
LATS1 | Large tumor suppressor kinase 1 |
LINC-ROR | Long intergenic non-protein coding RNA, regulator of reprogramming |
LINP1 | LncRNA in non-homologous end joining pathway 1 |
LLPS | Liquid-liquid phase separation |
LncRNA | Long noncoding ribonucleic acid |
lncRNA-ATB | LncRNA-activated by TGF-β |
LncPRESS1 | LncRNA p53-regulated and ESC-associated |
LSD1 | Lysine-specific histone demethylase 1 |
M6A | N6-methyladenosine |
MAFLD | Metabolic dysfunction-related fatty liver disease |
MALAT1 | Metastasis associated lung adenocarcinoma transcript 1 |
MAPK | Mitogen-activated protein kinase |
MATR3 | Matrin 3 |
MBNL3 | Muscleblind like splicing regulator 3 |
MCM2 | Minichromosome maintenance complex component 2 |
MEG3 | Maternally expressed 3 |
MEK | MAP kinase-ERK kinase |
MELTF-AS1 | MELTF antisense RNA 1 |
MEX3B | Mex-3 RNA-binding family member B |
miRNA | microRNA |
MMP | Matrix metallopeptidase |
MMTV-PyMT | mouse mammary tumor virus (MMTV) long terminal repeat upstream of a cDNA sequence encoding the Polyoma Virus middle T antigen (PyMT) |
MRI | Magnetic resonance imaging |
MTCH2 | Mitochondrial carrier 2 |
mTOR | Mammalian target of rapamycin |
MVIH | LncRNA associated with microvascular invasion in HCC |
MYC | MYC proto-oncogene, bHLH transcription factor |
NAFLD | Non-alcoholic fatty liver disease |
NASH | Non-alcoholic steatohepatitis |
NcRNA | Noncoding ribonucleic acid |
ND3 | NADH dehydrogenase subunit 3 |
NEAT1 | Nuclear paraspeckle assembly transcript 1 |
NF-κB | Nuclear factor kappa-light-chain-enhancer of activated B cells |
NHEJ | Non-homologous end joining |
NIHCOLE | Noncoding RNA induced in hepatocellular carcinoma with an oncogenic role in ligation efficiency |
NONO | Non-POU domain-containing octamer binding protein |
NOP2 | NOP2 nucleolar protein |
NORAD | Noncoding RNA activated by DNA damage |
NRAS | NRAS proto-oncogene, GTPase |
NSCLC | Non-small cell lung cancer |
PAARH | Progression and angiogenesis associated RNA in HCC |
PD-1 | Programmed cell death 1 |
PD-L1 | Programmed cell death 1 ligand 1 |
PDX | Patient-derived xenograft |
PGK1 | Phosphoglycerate kinase 1 |
PHAROH | Pluripotency and hepatocyte associated RNA overexpressed in HCC |
PHF8 | PHD finger protein 8 |
PI3K | Phosphatidylinositol 3-kinase |
PNCTR | Pyrimidine-rich noncoding transcript |
PNUTS | Phosphatase 1 nuclear targeting subunit |
Pol I | RNA polymerase I |
Pol II | RNA polymerase II |
Pol III | RNA polymerase III |
PPARA | Peroxisome proliferator–activated receptor alpha |
PPP1CA | Protein phosphatase 1 catalytic subunit alpha |
PRAL | p53 regulation-associated lncRNA |
PRC2 | Polycomb Repressive Complex 2 |
PRR34-AS1 | PRR34 antisense RNA 1 |
PTBP1 | Pyrimidine tract binding protein 1 |
PTEN | Phosphatase and tensin homolog |
PUM1 | Pumilio RNA-binding family member 1 |
PUM2 | Pumilio RNA-binding family member 2 |
PVT1 | Pvt1 oncogene |
PVTT | Portal vein tumor thrombus |
PXN-AS1 | Paxillin antisense RNA 1 |
RAB35 | RAB35, member RAS oncogene family |
RBP | RNA-binding protein |
RFA | Radiofrequency ablation |
RMST | Rhabdomyosarcoma 2 associated transcript |
RNA | Ribonucleic acid |
RNase | Ribonuclease |
RNAi | RNA interference |
RNP | Ribonucleoprotein |
RPS6KB1 | Ribosomal protein S6 kinase B1 |
RXRA | Retinoid X receptor alpha |
SAT1 | Spermidine/spermine N1-acetyltransferase 1 |
SCARNA10 | Small cajal body specific RNA 10 |
SERPINH1 | Serpin family H member 1 |
SET1 | Histone methyltransferase SET1 |
SETD2 | SET domain containing 2, histone lysine methyltransferase |
SF3B3 | Splicing factor 3b subunit 3 |
SFPQ | Splicing factor proline and glutamine rich |
shRNA | Short hairpin RNA |
siRNA | Small interfering RNA |
SIRT1 | Sirtuin 1 |
SIRT6 | Sirtuin 6 |
SLERT | Box H/ACA small nucleolar RNA (snoRNA)–ended lncRNA |
SNAIL | Zing-finger transcription factor Snail |
SNAP23 | Synaptosome associated protein 23 |
SNHG6 | Small nucleolar RNA host gene 6 |
SNHG9 | Small nucleolar RNA host gene 9 |
snRNA | Small nuclear RNA |
snoRNA | Small nucleolar RNA |
SOCS2 | Suppressor of cytokine signaling 2 |
SOX2 | SRY-box transcription factor 2 |
SOX12 | SRY-box transcription factor 12 |
SPHK1 | Sphingosine kinase 1 |
SR | Serine/arginine |
SREBP1 | Sterol regulatory element binding protein 1 |
STAT1 | Signal transducer and activator of transcription 1 |
STAT3 | Signal transducer and activator of transcription 3 |
SUZ12 | SUZ12 polycomb repressive complex 2 subunit |
TACE | Transarterial chemoembolization |
TAK1 | Transforming growth factor-β-activated kinase 1 |
TARID | TCF21 antisense RNA inducing promoter demethylation |
TCF7L2 | Transcription factor 7 like 2 |
TCF21 | Transcription factor 21 |
TDP-43 | Tar DNA binding protein |
TERT | Telomerase reverse transcriptase |
TET1 | Tet methylcytosine dioxygenase 1 |
TEX10 | Testis expressed 10 |
TGF-β | Transforming growth factor-β |
TGFBR2 | Transforming growth factor-β receptor 2 |
TIAR | TIA1 cytotoxic granule associated RNA-binding protein like 1 |
TKI | Tyrosine kinase inhibitor |
TNBC | Triple negative breast cancer |
TP53 | Tumor protein p53 |
TRAF6 | TNF receptor associated factor 6 |
Treg | Regulatory T cells |
TRERNA1 | Translation regulatory lncRNA 1 |
TUG1 | Taurine upregulated gene 1 |
URB1-AS1 | URB1-antisense RNA 1 |
USP22 | Ubiquitin-specific peptidase 22 |
VAMP3 | Vesicle associated membrane protein 3 |
VLP | Virus-like particles |
VEGF | Vascular endothelial growth factor |
VLDLR | Very low density lipoprotein receptor |
WDR5 | WD repeat domain 5 |
WTAP | WT1 associated protein |
XIST | X inactive specific transcript |
YAP1 | Yes1 associated transcriptional regulator |
YBX1 | Y-box binding protein 1 |
ZBTB7A | Zinc finger and BTB domain containing 7A |
ZEB1 | Zinc finger E-box binding homeobox 1 |
ZEB2 | Zinc finger E-box binding homeobox 2 |
ZFAS1 | ZNFX1 antisense RNA 1 |
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lncRNAs | Associated Protein | Mechanism | Phenotypes/Outcomes | References |
---|---|---|---|---|
DIGIT | BRD3 | Forms phase-separated condensates of BRD3, facilitating the histone H3 acetylation of lysine 18 (H3K18ac) of enhancers of endoderm transcription factors | Endoderm differentiation | [57] |
SLERT | DDX21 | Formation of fibrillar center (FC) and dense fibrillar component (DFC) in the nucleolus | RNA polymerase I (Pol I) transcription and ribosomal RNA production | [58,59] |
NORAD | PUM1 and PUM2 | Sequestration of Pumilio proteins in PUM condensates termed NP bodies | Inhibition of Pumilio function, preventing aberrant mitosis and maintaining genomic stability | [60] |
SNHG9 | LATS1 | LATS1 phase separation inhibits LATS1-mediated YAP phosphorylation | Activates YAP-driven gene transcription, thus promoting breast cancer | [61] |
MELTF-AS1 | YBX1 | Phase separation of oncogenic RBP YBX1 | Activation of ANXA8 transcription, leading to promotion of non-small-cell lung cancer (NSCLC) | [62] |
LINP1 | Ku70/Ku80 | Multimerization of Ku to form filamentous Ku-containing aggregates | Facilitates Ku-mediated DNA repair by non-homologous end joining (NHEJ) | [63] |
dilncRNA | DNA-damage-response (DDR) proteins, such as 53BP1 | Molecular crowding of DDR proteins in LLPS condensates | Facilitates DNA double-strand break (DSB) repair | [64] |
XiST | PTBP1, MATR3, TDP-43 and CELF1 RBPs | Forms a condensate in the inactive X (Xi)-compartment | X-chromosome inactivation | [65] |
GIRGL | CAPRIN1 | Sequesters CAPRIN1 and GLS1 mRNA in stress granules | Inhibition of GLS1 mRNA translation, facilitating the survival of cancer cells under glutamine-deprived conditions | [66] |
NEAT1 | TDP-43 | Formation of nuclear bodies in response to stress | Mitigation of stress, the dysfunction of which might be a cause of ALS | [67] |
lncRNAs | Expression | Role in HCC | Outcome in HCC | References |
---|---|---|---|---|
HOTAIR | Upregulated | Oncogene | Promotes metastasis | [38,84,85] |
MALAT1 | Upregulated | Oncogene | Promotes proliferation, migration, invasion, and metastasis | [86,87,88] |
HULC | Upregulated | Oncogene | Promotes proliferation and inhibits apoptosis | [85,89,90] |
GAS5 | Downregulated | Tumor Suppressor | Suppresses proliferation and invasion | [88,91] |
PVT1 | Upregulated | Oncogene | Promotes proliferation, migration, and invasion | [92,93,94] |
HOTTIP | Upregulated | Oncogene | Promotes proliferation and angiogenesis | [95,96,97] |
MVIH | Upregulated | Oncogene | Promotes proliferation, invasion, metastasis and angiogenesis | [98,99] |
H19 | Upregulated | Oncogene | Promotes proliferation, metastasis and angiogenesis | [99,100,101] |
MEG3 | Downregulated | Tumor suppressor | Inhibits proliferation, migration and invasion | [102,103] |
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Shah, M.; Sarkar, D. HCC-Related lncRNAs: Roles and Mechanisms. Int. J. Mol. Sci. 2024, 25, 597. https://doi.org/10.3390/ijms25010597
Shah M, Sarkar D. HCC-Related lncRNAs: Roles and Mechanisms. International Journal of Molecular Sciences. 2024; 25(1):597. https://doi.org/10.3390/ijms25010597
Chicago/Turabian StyleShah, Mimansha, and Devanand Sarkar. 2024. "HCC-Related lncRNAs: Roles and Mechanisms" International Journal of Molecular Sciences 25, no. 1: 597. https://doi.org/10.3390/ijms25010597