Circular RNAs in hepatocellular carcinoma: Recent advances

Table 1 Roles of circular RNAs in hepatocellular carcinoma

circRNAs	Dysregulation	Mechanism by competitively binding miRNAs/RBP or m6A modification/mRNA braking	Targets/signaling pathways	Biological functions	Ref.
circRNA ZFR	Up-regulated	N/A	MAP2K1	Promotes HCC proliferation	Cedric et al[50]
		miR-3619-5p	CTNNB1 Wnt/β-catenin pathway	Promotes HCC proliferation and EMT	Tan et al[99]
hsa_circ_0091581	Up-regulated	miR-526b	c-Myc	Promotes HCC proliferation	Wei et al[53]
circ_0000517	Up-regulated	miR-1296-5p	TXNDC5	Promotes HCC growth and inhibits cell cycle arrest and apoptosis	Zang et al[55]
		miR-326	SMAD6	Promotes HCC invasion and metastasis	He et al[67]
circSETD3	Down-regulated	miR-421	MAPK14	Inhibits HCC proliferation and induces G1/S arrest	Xu et al[57]
		N/A	N/A	Predicts MVI of HCC	Wang et al[85]
Exosomal circ-0051443	Down-regulated	miR-331-3p	BAK1	Promotes HCC cell apoptosis and arrests the cell cycle	Chen et al[58]
cicrRNA_101368	Up-regulated	miR-200a	HMGB1/RAGE pathway	Promotes HCC cell migration	Li et al[60]
circ-CCND1	Up-regulated	miR-497-5p	HMGA2	Promotes HCC proliferation, migration and invasion	Zheng et al[61]
hsa_circ_0061395	Up-regulated	miR-877-5p	PIK3R3	Promotes HCC proliferation, migration and invasion	Yu et al[62]
		miR-656-3p	SERBP1		Li et al[63]
circRNA-103809	Up-regulated	miR-377-3p	FGFR1/ERK	Facilitates HCC migration, invasion and EMT	Zhan et al[64]
		miR-1270	PLAGL2		Cao et al[65]
circ_MMP2	Up-regulated	miR-136-5p	MMP2	Promotes HCC metastasis	Liu et al[68]
circ-MALAT1	Up-regulated	mRNA braking	PAX5	Promotes self-renewal of HCC stem cells	Chen et al[69]
		miR-6887-3p	JAK2
circZKSCAN1	Down-regulated	RBP: FMRP	CCAR1, Wnt/β-catenin pathway	Inhibits HCC stem cell activity	Zhu et al[70]
circMEG3	Down-regulated	m6A-METTL3	HULC and Cbf5	Inhibits malignant differentiation of human liver CSCs	Jiang et al[71]
circ-PRKCI	Up-regulated	miR-1294 and miR-186-5p	FOXK1	Promotes HCC glycolysis	Chen et al[73]
circZFR	Up-regulated	miR-375	HMGA2	Promotes HCC glycolysis	Xu et al[75]
circMAT2B	Up-regulated	miR-338-3p	PKM2	Promotes HCC glycolysis	Li et al[77]
circ-PRMT5	Up-regulated	miR-188-5p	HK2	Enhances HCC glycolysis	Ding et al[79]
circ_0001445	Down-regulated	miR-942-5p	ALX4	Inhibits HCC metastasis and EMT	Xu et al[81]
ciRS-7	Up-regulated	miR-7	PIK3CD/p70S6K/mTOR pathway	Predicts hepatic MVI	Xu et al[83]
hsa_circ_0068669	Down-regulated	N/A	N/A	Predicts hepatic MVI	Yao et al[84]
circCRIM1	Up-regulated	miR-378a-3p	SKP2	Promotes HCC angiogenesis	Ji et al[86]
hsa-circ-0046600	Up-regulated	miR-640	HIF-1α	Promotes HCC angiogenesis	Zhai et al[87]
hsa_circ_0000092	Up-regulated	miR-338-3p	HN1	Promotes HCC angiogenesis	Pu et al[89]
circGFRA1	Up-regulated	miR-149	N/A	Promotes HCC angiogenesis	Yu et al[91]
circARSP91	Down-regulated	N/A	ULBP1	Enhances HCC innate immune surveillance	Ma et al[93]
circTRIM33-12	Down-regulated	miR-191	TET1	Inhibits HCC immune escape	Zhang et al[96]
hsa_circ0007456	Down-regulated	miR-6852-3p	ICAM-1	Inhibits HCC immune escape	Shi et al[97]
hsa_circ_104348	Up-regulated	miR-187-3p	RTKN2 Wnt/β-catenin pathway	Promotes HCC resistance to sorafenib	Huang et al[100]
circβ-catenin	Up-regulated	Translation	Wnt/β-catenin pathway	Facilitates HCC cell growth	Liang et al[101]
hsa_circ_0004018	Down-regulated	miR-626	DKK3 Wnt/β-catenin pathway	Restrains HCC proliferation and migration	Zhu et al[102]
circRNA-ITCH	Down-regulated	miR-7 or miR-214	c-myc and cyclinD1Wnt/β-catenin	Inhibits HCC proliferation and apoptosis	Yang et al[103]
circ-0003418	Down-regulated	miR-7 and miR-383	Wnt/β-catenin pathway	Increases HCC sensitivity to cisplatin	Chen et al[104]
circ-IGF1R	Up-regulated	N/A	PI3K/AKT pathway	Promotes HCC cell proliferation	Fu et al[106]
hsa_circ_0079299	Down-regulated	N/A	CCNB1PI3K/Akt/mTOR pathway	Inhibits HCC growth	Zheng et al[107]
circSOD2	Up-regulated	miR-502-5p	DNMT3A JAK2/STAT3 pathway	Promotes HCC growth, cell migration and cell cycle progression	Zhao et al[108]
circ_0004913	Down-regulated	miR-184	HAMP JAK2/STAT3/Akt pathway	Inhibits HCC proliferation, migration, invasion, EMT and glycolysis	Wu et al[109]
		N/A	N/A	Predicts better prognosis of HCC	Li et al[150]
circ_0031242	Up-regulated	miR-924	POU3F2	Enhances HCC resistance to cisplatin	Fan et al[112]
circARNT2	Up-regulated	miR-155-5p	PDK1	Promotes HCC resistance to cisplatin	Li et al[115]
circ-G004213	Down-regulated	miR-513b-5p	PRPF39	Facilitates HCC sensitivity to cisplatin	Qin et al[117]
circUBE2D2	Up-regulated	miR-889-3p	LDHA	Promotes HCC resistance to sorafenib	Huang et al[121]
circFN1	Up-regulated	miR-1205	E2F1	Facilitates HCC resistance to sorafenib	Yang et al[122]
circRNA-SORE	Up-regulated	RBP: YBX1	AKT, Raf1, ERK, c-Myc, and TGF-β1	Promotes HCC resistance to sorafenib	Xu et al[124]
circMEMO1	Down-regulated	miR-106b-5p	TCF21	Increases HCC sensitivity to sorafenib	Dong et al[126]
circUHRF1	Up-regulated	miR-449C-5p	TIM-3	Promotes HCC resistance to PD1 immunotherapy	Zhang et al[131]
circMET	Up-regulated	miR-30-5p	Snail/DPP4/CXCL10 axis	Promotes HCC resistance to PD1 immunotherapy	Huang et al[133]
Exosomal circ_0070396	Up-regulated	N/A	N/A	Serves as a biomarker of early diagnosis of HCC	Lyu et al[139]
circ_104075	Up-regulated	miR-582-3p	YAP	Serves as a biomarker of early diagnosis of HCC	Zhang et al[140]
has_circ _00224 and hsa_circ _00520	Up-regulated	N/A	N/A	Serves as biomarkers of early diagnosis of HCC with HCV infection	Matboli et al[141]
hsa_circ_0000976	Up-regulated	N/A	N/A	Serves as biomarkers of early diagnosis of HCC with HBV infection	Yu et al[142]
hsa_circ_0007750
hsa_circ_0139897
hsa_circ_0091579	Up-regulated	N/A	GPC3	Predicts poorer prognosis of HCC	Zhang et al[144]
circ_0000798		N/A	N/A		Lei et al[145]
circ_0000267	Up-regulated	miR-646	N/A	Predicts poorer prognosis of HCC	Pan et al[146]
circASAP1		miR-326, miR-532-5p	MAPK1		Hu et al[147]
circ-ZNF652	Up-regulated	miR-203/miR-502-5p	Snail-mediated EMT	Predicts poorer prognosis of HCC	Guo et al[148]
hsa_circ_0001649	Down-regulated	N/A	N/A	Predicts better prognosis of HCC	Zhang et al[149]
circSETD3	Down-regulated	miR-421	MMP1	Predicts better prognosis of HCC	Xu et al[57]
hsa_circ_0036683		N/A	N/A		Sunagawa et al[151]
hsa_circ_0005986	Down-regulated	N/A	N/A	Predicts better prognosis of HCC	Kim et al[152]

HCC: Hepatocellular carcinoma; ceRNA: Competitive endogenous RNA; CircRNAs: Circular RNAs; miRNAs: MicroRNAs; RBPs: RNA binding proteins; m⁶A: N6-methyladenosine; EMT: Epithelial-mesenchymal transition; MAP2K1: Mitogen-activated protein kinase 1; CTNNB1: Beta-catenin 1; Wnt/β-catenin: Wingless/beta-catenin; TXNDC5: Thioredoxin domain-containing 5; SMAD6: SMAD family member 6; MAPK14: Mitogen-activated protein kinase 14; MVI: Microvascular invasion; BAK1: BRI1-associated kinase 1; HMGB1/RAGE: High-mobility group box 1 protein/advanced glycation end products; HMGA2: High mobility group A2; PIK3R3: Phosphoinositide-3-kinase regulatory subunit 3; SERBP1: SERPINE1 mRNA binding protein 1; FGFR1/ERK: Fibroblast growth factor receptor 1/extracellular signal-regulated kinase; PLAGL2: PLAG1 like zinc finger 2; MMP2: Matrix metalloproteinase 2; PAX5: Paired box protein 5; AUF1: AU-rich binding factor 1; FMRP: Fragile X mental retardation protein; CCAR1: Cell division cycle and apoptosis regulator 1; METTL3: Methyltransferase-like 3; HULC: Highly upregulated in liver cancer; Cbf5: Centromere-binding factor 5; CSCs: Cancer stem cells; FOXK1: Forkhead box K1; PKM2: Pyruvate kinase M2; HK2: Hexokinase 2; ALX4: Aristaless-like homeobox 4; PIK3CD/p70S6K/mTOR: PI3Kdelta catalytic p110delta/Ribosomal protein S6 kinase/mammalian target of rapamycin; SKP2: S-phase kinase-associated protein 2; HIF-1α: Hypoxia inducible factor-1α; HN1: Hematological and neurological expressed 1; ULBP1: UL16-binding protein 1; TET1: Ten-eleven translocation 1; ICAM-1: Intercellular adhesion molecule-1; RTKN2: Rhotekin 2; DKK3: Dickkopf-3; PI3K/Akt: Phosphoinositide-3-kinase/protein kinase B; CCNB1: Cyclin B1; DNMT3A: DNA methyltransferase 3A; JAK/STAT: Janus kinases/signal transducer and activator of transcription; JAK2/Stat3: Janus kinase 2/signal transducers and activators of transcription; HAMP: Hepcidin; POU3F2: POU class 3 homeobox 2; PDK1: Pyruvate dehydrogenase kinase 1; PRPF39: Pre-mRNA splicing factor 39; LDHA: Lactate dehydrogenase A; E2F1: E2F transcription factor 1; YBX1: Y-box-binding protein 1; Raf1: Proto-oncogene serine/threonine-protein kinase-1; ERK: Extracellular signal-regulated kinase; TGF-β1: Transforming growth factor beta1; TCF21: Transcription factor 21; Tim-3: T cell immunoglobulin and mucin domain 3; PD1: Programmed cell death protein 1; DPP4: Dipeptidyl peptidase 4; CXCL10: Chemokine C-X-C ligand 10; Yap: Yes-associated protein; HCV: Hepatitis C virus; HBV: Hepatitis B virus; GPC3: Glypican-3 protein; MAPK1: Mitogen-activated protein kinase 1; MMP1: Matrix metallopeptidase 1; MAPK1: Mitogen-activated protein kinase 1; AFP: Alpha fetoprotein; AFP-L3: Alpha-fetoprotein variants; DCP: Des-carboxy prothrombin; OS: Overall survival; RFS: Recurrence-free survival; PFS: Progression-free survival; N/A: Not applicable.