New insights on the role of epigenetic alterations in hepatocellular carcinoma

Figures & data

Figure 1 Intranuclear and extranuclear phases of the process of maturation of microRNAs (miRNAs) and mechanisms of inhibition of messenger RNA transcription. In the nucleus, long primary transcripts (primary miRNAs) are cleaved by RNase III Drosha, with its cofactor Pasha, to release the precursor miRNAs, which are exported to the cytoplasm by exportin 5. In the cytoplasm, precursor miRNAs are processed by RNase III Dicer, with the release double-stranded duplexes of 20–23 RNA that contain the mature miRNA and the passenger miRNA strand (asterisked). The mature miRNAs interact with the 3′ untranslated region of its targeted mRNAs to form, with Argonaute proteins, the RNA-induced silencing complex (RISC). RISC binds to the 3′ untranslated region of its target or targets, inhibiting translation of single or multiple proteins; complete miRNA complementarity induces mRNA degradation, whereas partial complementarity represses translation.

Abbreviations: RAN, RAS-related nuclear protein; GTP, guanosine-5′-triphosphate; ORF, open reading frame.

Figure 2 Methionine metabolism.

Abbreviations: ODC, ornithine decarboxylase; ATP, adenosine triphosphate; SRS, spermine synthase; 5′-MTA, 5′-methylthioadenosine; SDC, SAM decarboxylase; SAM, S-adenosylmethionine; Dec-SAM, decarboxylated SAM; SPD, spermidine; MAT, methionine adenosyltransferase; SDS, spermidine synthase; THF, tetrahydrofolate; DMGN, dimethyl GN; GN, glycine; SPR, spermine; DMTHF, dimethyl-THF; MTHF-HMT, 5-methyltetrahydrofolate homocysteine methyltransferase; BHMT, betaine-homocysteine methyltransferase; GNMT, glycine N-methyltransferase; MT, methyltransferase; MTHFR, methyltetrahydrofolate reductase; MTHF, methyl-THF; SN, sarcosine; X-CH₃, methylated compounds; SAHH, SAH hydrolase; SAH, S-adenosylhomocysteine; CBS, cystathionine beta-synthase.

Table 1 Targets and functional effects of microRNAs up-regulated in hepatocarcinogenesis

microRNA	Targets	Functional effects*	Reference
miR-423	P21/WAF1	Enhanced CDK2 activity (G1-S transition)	^Citation104
miR-221	P27/KIP1, p57/KIP2	Enhanced CDK2 activity (G1-S transition)	^Citation105
miR-93, miR-106b	E2F1	Prevention of excessive E2F1 accumulation (?)	^Citation112
miR-602	RASSF1A	Enhanced RAS/ERK, MST/YAP, pathways, JUN	^Citation106
miR-222	PP2A	Enhanced AKT pathway	^Citation107
miR-221, miR-222, miR-21	PTEN	Enhanced AKT pathway	^Citation108
miR-221	DDIT4	TSC1/2 complex inhibition and AKT activation	^Citation109
miR-221, miR-222 miR-181b/d	TIMP3	Enhanced MMP2 and MMP9	^Citation110
miR-221	BMF	Apoptosis inhibition	^Citation111
miR-106b, miR-93, miR-25	BIM	Apoptosis inhibition	^Citation112
miR-221, miR-222	TRAIL-induced apoptosis	Inhibition of caspases 3, 6, 7, 8	^Citation109
miR-192	ERCC3, ERCC4	Inhibition of DNA excision repair	^Citation115

Notes:

* Functional effects of miRNA up- or down-regulation.

Abbreviations: AKT, v-AKT murine thymoma viral oncogene homolog; BIM, BCL2 interacting protein; BMF, BCL2 modifying factor; CDK2, cyclin-dependent kinase 2; DDIT4, DNA damage-inducible transcript 4; E2F1, E2F transcription factor 1; ERCC3/4, excision-repair, complementing defective, in Chinese hamster, 3/4; ERK, extracellular signal regulated kinase; JUN, v-JUN avian sarcoma virus 17 oncogene homolog; KIP 1, cyclin-dependent kinase inhibitor 1; MMP, matrix metalloproteinase; MST, homologues of Hpo; PP2A, Protein phosphatase 2A; PTEN, Phosphatase and tensin homologue deleted on chromosome 10; RAS, rat sarcoma; RASSF1A, Ras association domain family 1A; TIMP3, tissue inhibitor of metalloproteinase 3; TRAIL, TNF-related apoptosis-inducing ligand; YAP, Yes kinase-associated protein.

Table 2 Targets and functional effects of microRNAs down-regulated in hepatocarcinogenesis

microRNA	Targets	Functional effects*	Reference
miR26a	Cycl D2, E2, IL6	Enhanced G1-S transition	^Citation26, ^Citation116
miR195	Cycl D1, CDK6, E2F3	Enhanced G1-S transition	^Citation117
miR-122	Cycl G1	Enhanced cell cycle progression	^Citation118
	PBF	Stimulation of HCC proliferation	^Citation119
miR-223	STMN1	Microtubules stabilization (G1-M transition)	^Citation120
Let-7G	Collagen 1-α2	Enhanced cell migration	^Citation122
miR-200b	ZEB1, ZEB2	Stimulation of EMT	^Citation123
miR-124	ROCK2, EZH2	Stimulation of EMT	^Citation124
miR-194	N-Cadherin	Stimulation of EMT	^Citation125
miR-148a	SNAIL, N-Cadherin	Stimulation of EMT	^Citation126,Citation127
miR-23b	uPA, c-MET	HCC cell migration	^Citation128
miR-139	ROCK2, c-FOS, TCF-4	HCC cell migration	^Citation129,Citation130, ^Citation132
miR-99a	IGF-1R, mTOR	Stimulation of HCC proliferation	^Citation133
miR-122	NDRG3	Stimulation of HCC proliferation	^Citation134
miR-375	AEG-1	Stimulation of HCC proliferation	^Citation135
	YAP	Stimulation of HCC proliferation	^Citation136
miR-338-3p	SMO	Stimulation of HCC proliferation	^Citation137
miR34a	c-MET	Stimulation of HCC proliferation	^Citation138
miR-203	SURVIVIN	Stimulation of HCC proliferation	^Citation139
miR-124	PIK3CA	Enhanced PI3K/AKT pathway	^Citation140
	STAT3	Enhanced STAT3 signaling	^Citation141
miR-637	STAT3	Enhanced STAT3 signaling	^Citation142
miR-491-5p	AFP, HSP90, NF-kB	Inhibition of TNF-α- related apoptosis	^Citation145
miR-145	HDAC2	Hepatocarcinogenesis promotion	^Citation143
	ADAM17	HCC metastases	^Citation146
miR-214	FGF-R1	HCC metastases	^Citation147
miR-22	HDAC4	Hepatocarcinogenesis promotion	^Citation144
miR-22 and	NCOA1, NRIP1	Apoptosis inhibition	^Citation152
miR-140-3-p
miR-122	BCL-W	Apoptosis inhibition	^Citation153
miR-29	BCL-2, MCL-1	Apoptosis inhibition	^Citation154
miR-101	MCL-1	Apoptosis inhibition	^Citation155
	DNMT3A	Enhanced methylation of oncosuppressors	^Citation157
miR-29c	TNFAIP3	Apoptosis inhibition	^Citation156
miR-152	DNMT1	Hypermethylation of GSTP1, CDH1	^Citation158

Notes:

* Functional effects of miRNA up- or down-regulation.

Abbreviations: ADAM17, a disintegrin and metalloproteinase domain 17; AEG-1, astrocyte elevated gene-1; AFP, alpha-fetoprotein; AKT, v-AKT murine thymoma viral oncogene homolog; BCL-2, B-CELL CLL/Lymphoma 2; BCL-W, BCL-like 2; CDH1, cadherin 1; CDK6, cyclin-dependent kinase 6; c-FOS, FBJ murine osteosarcoma viral oncogene homolog; c-MET, hepatocyte growth factor receptor; Cycl D1, D2, E, G1, Cyclin D1, D2, E, G1; DNMT1, 3A, DNA methyltransferase1, 3A; E2F3, E2F transcription factor 3; EMT, epithelial-mesenchymal transition; EZH2, enhancer of ZESTE, drosophila, homolog 2; FGF-R1, fibroblast growth factor, receptor 1; GSTP1, glutathione S-transferase P1; HCC, hepatocellular carcinoma; HDAC, histone deacetylase; HSP90, heat shock protein 90; IGF-1R, Insulin-like growth factor, receptor 1; IL6, interleukin 6; MCL-1, myeloid cell leukemia sequence 1; mTOR, mammalian target of rapamycin; NCOA1, nuclear receptor coactivator 1; NDRG3, NMYC downstream-regulated gene 3; NF-kB, nuclear factor kB; NRIP1, nuclear receptor-interacting protein 1; PBF, pituitary tumor-transforming gene binding factor; PI3K, phpsphatidylinositol 3 kinase; PIK3CA, phosphatidylinositol 3-kinase, catalytic, alpha; ROCK2, RHO-associated coiled-coil-containing protein kinase 2; SMO, smoothened; STAT3, signal transducer and activator of transcription 3; STMN1, stathmin 1; TCF-4, T cell factor 4; TNFAIP3, tumor necrosis factor alpha-induced protein 3; uPA, plasminogen activator, urinary; YAP, yes associated protein 1; ZEB1/2, zinc finger E box-binding homeobox 1/2.

Figure 3 Transcriptional, translational, and posttranslational mechanisms leading to deregulation of MAT1A, tumor suppressor genes, and oncogenes during hepatocarcinogenesis.

Abbreviations: miRNAs, microRNAs; MAT1A, methionine adenosyltransferase IA; HCC, hepatocellular carcinoma; GI, genomic instability.

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