Behind the curtain of non-coding RNAs; long non-coding RNAs regulating hepatocarcinogenesis

Table 1 Interplay between long non-coding RNAs and miRNAs

lncRNA	miRNA	Effect/ relationship	Pathway
HULC	miR-6825-5p, miR-6845-5p, miR-6886-3p	Inhibitory	Increasing chemotherapy sensitivity through USP22 and sirt1 levels controlling autophagy
	miR-200a-3p	Inhibitory	Increasing ZEB1 expression, EMT and metastasis
	miR-107	Inhibitory	Upregulates E2F1, activates SPHK1 and angiogenesis
	miR-203	Inhibitory	Inhibits cellular proliferation and induces apoptosis
	miR-9 (ZNFX1-AS1)	Inhibitory	Positive feedback loop of HULC/miR-9/PPARA/ACSL1/HULC for lipid metabolism regulation
	miR-372 (PCAT-14)	Inhibitory	Auto-regulatory loop of CREB/HULC/miR-372/PRKACB/CREB/HULC enhancing cellular proliferation
XIST	miR-181a	Inhibitory	Binds to several binding sites on miR-181a modulating its function
	miR-92b	Inhibitory	Suppresses miR-92b/Smad7 oncogenic axis
	miR-139-5p	Inhibitory	Modulate the miR-139-5p/PDK1/AKT axis
CCAT1	Let-7	Inhibitory	Restoring HMGA2 and c-myc levels and enhancing cell proliferation
	miR-490-3p	Inhibitory	Regulate CDK1 and HCC proliferation
AF113014	miR-20a	Interaction	Regulate Erg2 expression
CRNDE	miR-384	Inhibitory	Enhances expression of NF-κB and p-AKT
DANCR	miR-214, miR-320a, miR-199a	Cancels its effect	Cancels the inhibitory effect they exert on CTNNB1 hence enhancing tumorigenesis
FTX	miR-374a	inhibitory	represses Wnt/β-catenin signaling pathway
	miR-545	interaction	Tumor promotor through activation of PI3K/Akt
GAS5	miR-21	inhibitory	downregulated the vimentin level and the upregulated E-cadherin level
GIHCG	miR-200a/b/429	Inhibitory	Associates with EZH2 and silences miRNA
H19	miR-200	activation	tumor-suppressive by mediating hnRNPU/PCAF/RNAPol II
	miR-675	inhibitory	Activation of the AKT/ GSK-3β/Cdc25A signaling pathway
HOTAIR	miR-1	Inhibitory
	miR-218	Inhibitory	Inhibits P16(lnk4a) and P14(ARF) expression, activates Bmi-1 and tumorigenesis
HOTTIP	miR-192, miR-204	Negative	Inhibit HOTTIP expression, GLS1 and HCC proliferation
	miR-125b	Negative	Inhibits HOTTIP expression and HOXA genes
Linc00052	miR-128, miR-485-3p	Complementary base pairing	Modulating NTRK3 expression
Linc-ROR	miR-145	Inhibitory	Enhances HIF-1α/PDK1 expression
MALAT-1	miR-143-3p	inhibitory	regulated ZEB1 expression
	miR-146b-5p	inhibitory	targeting TRAF6 mediated Akt phosphorylation
MEG-3	miR-29a	interaction	modulate DNMT 1 and 3
	miR-26a	Negative	Modulates miR-26a/DNMT3B/MEG3
NEAT1	miR-129-5p	Inhibitory	Inhibits the miRNA through regulating VCP/IκB, its downstream pathway
lincRNA-p21	miR-9	inhibitory	Tumor suppressive
PCAT-14	miR-372 (HULC)	Inhibitory	Regulates ATAD2 and hedgehog pathway
PTENP1	miR-17, miR-19b, miR-20a	Inhibitory	Inhibiting PIK3T/AKT pathway and inducing autophagy
PVT1	miR-186-5p	Inhibitory	Restores YAP1 expression levels
SNHG1	miR-195	Inhibitory
SNHG6	miR-26a, miR-26b	Inhibitory	Modulate TAK1 expression
SNHG12	miR-199a/b-5p	Inhibitory	ceRNA, Enhancing MLK3 expression and NF-κB pathway
TP73-AS1	miR-200a	Inhibitory	miR-200a dependent HMGB1/RAGE regulation
UCA1	miR-203	interaction	UCA1/miR203/Snail2 signaling pathway regulatory network
	miR-216b	inhibitory	activation of FGFR1/ERK signaling pathway
Unigene56159	miR-140-5p	Inhibitory	ceRNA, Restoring slug expression and EMT
ZNFX1-AS1	miR-9	Positive	Tumor suppression

HOTTIP: HOXA transcript at the distal TIP; lncRNAs: Long non-coding RNAs; PCAT: Prostate cancer-associated transcript; HULC: Highly up-regulated in liver cancer; XIST: X-inactive specific transcript; TCF7: Transcription factor 4; TUG1: Taurine upregulated gene 1; EGFR: Epidermal growth factor receptor; CCAT1: Colon cancer associated transcript 1; MALAT1: Metastasis-associated lung adenocarcinoma transcript 1; UCA1: Urothelial carcinoma-associated 1; SPRY4-IT: Sprouty 4-intron transcript; SNHG: Small nucleolar rna host gene.

Table 2 Different models used in studies

lncRNA	Study	Model	Ref.
HULC	Molecular mechanism of HEIH and HULC in the proliferation and invasion of hepatoma cells.	In vitro	[104]
	lncRNA HULC promotes the growth of hepatocellular carcinoma cells via stabilizing COX-2 protein	In vitro	[105]
	lncRNA HULC triggers autophagy via stabilizing Sirt1 and attenuates the chemosensitivity of HCC cells.	In vitro and in vivo (nude mice)	[106]
	lncRNA HULC enhances epithelial-mesenchymal transition to promote tumorigenesis and metastasis of hepatocellular carcinoma via the miR-200a-3p/ZEB1 signaling pathway.	In vitro and in vivo (nude mice)	[107]
	lncRNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1)	In vitro and in vivo (nude mice)	[108]
	Specificity protein (Sp) transcription factors and metformin regulate expression of the long non-coding RNA HULC	In vitro	[109]
	miR-203 suppresses the proliferation and metastasis of hepatocellular carcinoma by targeting oncogene ADAM9 and oncogenic long non-coding RNA HULC.	In vitro	[110]
	Long noncoding RNA HULC modulates abnormal lipid metabolism in hepatoma cells through an miR-9-mediated RXRA signaling pathway.	In vitro and in vivo (nude mice)	[111]
	Long noncoding RNA HULC modulates the phosphorylation of YB-1 through serving as a scaffold of extracellular signal-regulated kinase and YB-1 to enhance hepatocarcinogenesis.	In vitro	[112]
HOTAIR	Clinical significance of the expression of long non-coding RNA HOTAIR in primary hepatocellular carcinoma.	In vitro	[117]
	Overexpression of long non-coding RNA HOTAIR predicts tumor recurrence in hepatocellular carcinoma patients following liver transplantation.	In vitro	[118]
	Long non-coding RNA HOTAIR is a marker for hepatocellular carcinoma progression and tumor recurrence.	In vitro and in vivo (nude mice)	[119]
	Large intervening non-coding RNA HOTAIR is associated with hepatocellular carcinoma progression	In vitro	[120]
	The long noncoding RNA HOTAIR activates autophagy by upregulating ATG3 and ATG7 in hepatocellular carcinoma	In vitro	[121]
	LncRNA HOTAIR promotes human liver cancer stem cell malignant growth through downregulation of SETD2	In vitro and in vivo (mice)	[122]
	HOTAIR, a long non-coding RNA driver of malignancy whose expression is activated by FOXC1, negatively regulates miRNA-1 in hepatocellular carcinoma.	In vitro and in vivo (mice)	[123]
	Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling.	In vitro and in vivo (mice)	[125]
	Long non-coding RNA HOTAIR promotes cell migration and invasion via down-regulation of RNA binding motif protein 38 in hepatocellular carcinoma cells.	In vitro	[126]
SNHG	SNHG3 correlates with malignant status and poor prognosis in hepatocellular carcinoma.	In vitro	[80]
	Long non-coding RNA small nucleolar RNA host gene 12 (SNHG12) promotes tumorigenesis and metastasis by targeting miR-199a/b-5p in hepatocellular carcinoma.	In vitro	[81]
	Long noncoding RNA SNHG15, a potential prognostic biomarker for hepatocellular carcinoma	In vitro	[82]
	Long noncoding RNA SNHG1 predicts a poor prognosis and promotes hepatocellular carcinoma tumorigenesis	In vitro	[187]
	Expression of Long Non-Coding RNA (lncRNA) Small Nucleolar RNA Host Gene 1 (SNHG1) Exacerbates Hepatocellular Carcinoma Through Suppressing miR-195	In vitro	[188]
	The long non-coding RNA, SNHG6-003, functions as a competing endogenous RNA to promote the progression of hepatocellular carcinoma.	In vitro	[190]
	Up-regulation of LncRNA SNHG20 Predicts Poor Prognosis in Hepatocellular Carcinoma.	In vitro	[191]
	Long non-coding RNA SNHG20 predicts a poor prognosis for HCC and promotes cell invasion by regulating the epithelial-to-mesenchymal transition.	In vitro	[192]
MALAT1	Long Non-Coding RNA MALAT1 Regulates ZEB1 Expression by Sponging miR-143-3p and Promotes Hepatocellular Carcinoma progression.	In vitro	[130]
	HBx-related long non-coding RNA MALAT1 promotes cell metastasis via up-regulating LTBP3 in hepatocellular carcinoma.	In vitro and in vivo (Male BALB/C nude mice)	[131]
	Down-regulation of miR-146b-5p by long noncoding RNA MALAT1 in hepatocellular carcinoma promotes cancer growth and metastasis.	In vitro and in vivo (nude mice)	[132]
	Long non-coding RNA MALAT-1 overexpression predicts tumor recurrence of hepatocellular carcinoma after liver transplantation.	In vitro	[133]
MEG3	Armored long non-coding RNA MEG3 targeting EGFR based on recombinant MS2 bacteriophage virus-like particles against hepatocellular carcinoma.	In vitro and in vivo (BALB/c nude mice)	[137]
	MicroRNA-26a inhibits proliferation and metastasis of human hepatocellular carcinoma by regulating DNMT3B-MEG3 axis.	In vitro	[138]
	Overexpression of Long Non-Coding RNA MEG3 Inhibits Proliferation of Hepatocellular Carcinoma Huh7 Cells via Negative Modulation of miRNA-664.	In vitro	[139]
	Long Noncoding RNA MEG3 Interacts with p53 Protein and Regulates Partial p53 Target Genes in Hepatoma Cells	In vitro	[141]
	The aberrant expression of MEG3 regulated by UHRF1 predicts the prognosis of hepatocellular carcinoma.	In vitro	[144]
	microRNA-29 can regulate expression of the long non-coding RNA gene MEG3 in hepatocellular cancer.	In vitro	[145]
AFAP1-AS1	Long noncoding RNA AFAP1-AS1 indicates a poor prognosis of hepatocellular carcinoma and promotes cell proliferation and invasion via upregulation of the RhoA/Rac2 signaling.	In vitro and in vivo (mice)	[148]
	Critical role for the long non-coding RNA AFAP1-AS1 in the proliferation and metastasis of hepatocellular carcinoma.	In vitro and in vivo (mice)	[147]
ANRIL	High expression of long non-coding RNA ANRIL is associated with poor prognosis in hepatocellular carcinoma.	In vitro	[149]
ATB	A long noncoding RNA activated by TGF-beta promotes the invasion metastasis cascade in hepatocellularcarcinoma.	In vitro and in vivo (nude mice)	[151]
CCAT1	Aberrant Expression of CCAT1 Regulated by c-Myc Predicts the Prognosis of Hepatocellular Carcinoma.	In vitro	[153]
	CCAT1 promotes hepatocellular carcinoma cell proliferation and invasion.	In vitro	[152]
	Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge.	In vitro	[154]
CCAT2	Long non-coding RNA CCAT2 is associated with poor prognosis in hepatocellular carcinoma and promotes tumor metastasis by regulating Snail2-mediated epithelial-mesenchymal transition.	In vitro	[157]
	Long non-coding RNA CCAT2 functions as an oncogene in hepatocellular carcinoma, regulating cellular proliferation, migration and apoptosis	In vitro	[156]
DANCR	Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1.	In vitro and in vivo (mice)	[159]
	DANCR Acts as a Diagnostic Biomarker and Promotes Tumor Growth and Metastasis in Hepatocellular Carcinoma	In vitro and in vivo (mice)	[158]
EGFR	The long noncoding RNA, EGFR-AS1, a target of GHR, increases the expression of EGFR in hepatocellular carcinoma.	In vitro and in vivo	[160]
FTX	Ftx non coding RNA-derived miR-545 promotes cell proliferation by targeting RIG-I in hepatocellular carcinoma.	In vitro and in vivo (nude mice)	[163]
GAS-5	Decreased expression of long non-coding RNA GAS5 indicates a poor prognosis and promotes cell proliferation and invasion in hepatocellular carcinoma by regulating vimentin.	In vitro	[165]
	Down-regulation of long non-coding RNA GAS5 is associated with the prognosis of hepatocellular carcinoma.	In vitro	[164]
H19	Epigenetic activation of the MiR-200 family contributes to H19-mediated metastasis suppression in hepatocellular carcinoma.	In vitro and in vivo (Nude mice)	[169]
HOTTIP	Long non-coding RNA HOTTIP is frequently up-regulated in hepatocellular carcinoma and is targeted by tumour suppressive miR-125b.	In vivo (mice)	[174]
	MiRNA-192 [corrected] and miRNA-204 Directly Suppress lncRNA HOTTIP and Interrupt GLS1-Mediated Glutaminolysis in Hepatocellular Carcinoma.	In vitro and in vivo (mice)	[173]
	Long noncoding RNA HOTTIP/HOXA13 expression is associated with disease progression and predicts outcome in hepatocellular carcinoma patients.	In vitro	[172]
Linc00152	LINC00152 promotes proliferation in hepatocellular carcinoma by targeting EpCAM via the mTOR signaling pathway.	In vitro and in vivo (mice)	[178]
NEAT1	Long non-coding RNA NEAT1 promotes hepatocellular carcinoma cell proliferation through the regulation of miR-129-5p-VCP-IκB.	In vitro and in vivo (mice)	[176]
	Long noncoding RNA NEAT1 promotes cell proliferation and invasion by regulating hnRNP A2 expression in hepatocellular carcinoma cells.	In vitro and in vivo (mice)	[177]
P21	lincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through Notch signaling-induced epithelial-mesenchymal transition.	In vitro and in vivo (nude mice)	[180]
	LincRNA-p21 inhibits invasion and metastasis of hepatocellular carcinoma through miR-9/E-cadherin cascade signaling pathway molecular mechanism.	In vitro	[181]
PCAT1	Upregulation of long non coding RNA PCAT-1 contributes to cell proliferation, migration and apoptosis in hepatocellular carcinoma.	In vitro	[182]
	Prognostic significance of long non-coding RNA PCAT-1 expression in human hepatocellular carcinoma.	In vitro	[183]
PRAL	Systemic genome screening identifies the outcome associated focal loss of long noncoding RNA PRAL in hepatocellular carcinoma	In vitro and in vivo (mice)	[44,209]
PVT1	Long non-coding RNA PVT1 serves as a competing endogenous RNA for miR-186-5p to promote the tumorigenesis and metastasis of hepatocellular carcinoma.	In vitro	[186]
	Oncofetal long noncoding RNA PVT1 promotes proliferation and stem cell-like property of hepatocellular carcinoma cells by stabilizing NOP2.	In vitro and in vivo (mice)	[185]
SPRY4-IT1	Overexpression of the long non-coding RNA SPRY4-IT1 promotes tumor cell proliferation and invasion by activating EZH2 in hepatocellular carcinoma	In vitro	[210]
TCF7	Long noncoding RNA lncTCF7, induced by IL-6/STAT3 transactivation, promotes hepatocellular carcinoma aggressiveness through epithelial-mesenchymal transition	In vitro	[200]
	The long noncoding RNA lncTCF7 promotes self-renewal of human liver cancer stem cells through activation of Wnt signaling.	In vitro	[201]
TUG1	Long non-coding RNA TUG1 is up-regulated in hepatocellular carcinoma and promotes cell growth and apoptosis by epigenetically silencing of KLF2.	In vitro	[195]
UCA1	HBx-upregulated lncRNA UCA1 promotes cell growth and tumorigenesis by recruiting EZH2 and repressing p27Kip1/CDK2 signaling	In vitro	[203]
	Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway.	In vitro and in vivo (Mice)	[204]
XIST	Long non-coding RNA XIST regulates PTEN expression by sponging miR-181a and promotes hepatocellular carcinoma progression.	In vitro	[206]
	MicroRNA-92b promotes hepatocellular carcinoma progression by targeting Smad7 and is mediated by long non-coding RNA XIST	In vitro and in vivo (mice)	[207]
	Long non-coding RNA XIST promotes cell growth by regulating miR-139-5p/PDK1/AKT axis in hepatocellular carcinoma.	In vitro and in vivo (mice)	[208]

HOTTIP: HOXA transcript at the distal TIP; lncRNAs: Long non-coding RNAs; PCAT: Prostate cancer-associated transcript; HULC: Highly up-regulated in liver cancer; XIST: X-inactive specific transcript; TCF7: Transcription factor 4; TUG1: Taurine upregulated gene 1; EGFR: Epidermal growth factor receptor; CCAT1: Colon cancer associated transcript 1; MALAT1: Metastasis-associated lung adenocarcinoma transcript 1; UCA1: Urothelial carcinoma-associated 1; SPRY4-IT: Sprouty 4-intron transcript; SNHG: Small nucleolar rna host gene.