Circular RNAs as Novel Biomarkers with Regulatory Potency in Human Diseases

Figures & data

Figure 1.  Regulatory functions of different types of circular RNAs.

(A–C) Three types of circular RNAs (circRNAs). (A) EcircRNAs are generated from exons. (B) EIcircRNAs contain both exons and introns. (C) CircRNAs are formed by introns. (D–G) Functions of circRNAs. (D) CircRNAs can act as miRNA sponges. (E) CircRNAs are able to promote transcription. (F) CircRNAs can bind to proteins. (G) CircRNAs encode proteins.

CircRNA: Circular intronic RNA; EcircRNA: Exonic RNA; EIcircRNA: exon–intron RNA.

Table 1. Circular RNAs classification and function.

Type	Derivation	Location	Function	Examples	Ref.
EcircRNA	Exons	Mainly cytoplasm	MiRNA sponge; cis-regulation at post-transcriptional level; protein binding; encode functional proteins	Cdr1as; circ-ITCH; hsa_circ_0031288; circ-FBXW7	[10,26–28]
EIcircRNA	Exons and introns	Mainly nucleus	Cis-regulation of parent gene	circEIF3J; circPAIP2	[5]
CircRNA	Introns	Mainly nucleus	Cis-regulation of parent gene	circ-ankrd52; circ-mcm5; circ-sirt7	[6]

CircRNA: Circular intronic RNA; EcircRNA: Exonic RNA; EIcircRNA: exon–intron RNA.

Table 2. Circular RNAs in nontumor diseases.

Disease	CircRNA	Target	Method involved	Expression	Function	Ref.
Atherosclerosis	circANRIL	PES1 protein	PCR and RT-qPCR	Decrease	Atheroprotective	[38]
	hsa_circ_0003575	–	Microarray analysis; RT-qPCR	Increase	Repress endothelial cell proliferation and angiogenesis	[43]
CAD	circ11783–2	–	Microarray analysis; RT-qPCR	Decrease	Potential biomarker for CAD combined with T2DM	[44]
MI and heart failure	circMFACR	miR-652–3p/MTP18	PCR and RT-qPCR	Increase	Promote apoptosis and MI	[45]
	MICRA	–	RT-qPCR	Decrease	Potential biomarker for risk stratification	[46]
Hypertension	hsa_circ_0005870	–	Microarray analysis; RT-qPCR	Decrease	Potential biomarker for hypertension diagnosis	[47]
Myocardial fibrosis	circ_000203	miR-26b-5p/Col1a2, CTGF	Microarray analysis; PCR; RT-qPCR	Increase	Promote fibrosis	[48]
	circ_010567	miR-141/TGF-β1	Microarray analysis; RT-qPCR	Increase	Promote fibrosis	[49]
Cardiac hypertrophy	circHRCR	miR-223/ARC	RT-qPCR	Decrease	Repress cardiac hypertrophy	[50]
Diabetes mellitus and prediabetes	hsa_circ_0054633	–	Microarray analysis; RT-qPCR	Increase	Potential biomarker for T2DM and prediabetes diagnosis	[13]
DR	circ_0005015	miR-519d-3p	Microarray analysis; RT-qPCR	Increase	Potential biomarker for DR diagnosis; promote proliferation	[51]
	circHIPK3	miR-30a-3p/VEGFC, WNT2, FZD4	RT-qPCR	Increase	Promote proliferation and vascular dysfunction	[33]
RA	circRNA_104871	–	Microarray analysis; RT-qPCR	Increase	Potential biomarker for RA diagnosis	[52]
LN	circHLA-C	miR-150	RNA-seq; RT-qPCR	Increase	Potential biomarker for LN diagnosis	[53]

CAD: Coronary artery disease; circANRIL: Circular ANRIL; CircRNA: Circular RNA; DR: Diabetic retinopathy; LN: Lupus nephritis; MI: Myocardial infarction; RA: Rheumatoid arthritis; RT-qPCR: Reverse transcription-quantitative polymerase chain reaction; T2DM: Type 2 diabetes mellitus.

Table 3. Circular RNAs in cancers.

Disease	CircRNA	Target	Method involved	Expression	Function	Ref.
Lung cancer	hsa_circ_000064	–	RT-qPCR	Increase	Potential biomarker for lung cancer diagnosis; promote proliferation and invasion	[68]
	circRNA_100876	–	RT-qPCR	Increase	Potential biomarker for NSCLC diagnosis	[69]
	hsa_circ_0014130	–	Microarray analysis; RT-qPCR	Increase	Potential biomarker for NSCLC diagnosis	[70]
	hsa_circ_0013958	miR-134/CCND1	Microarray analysis; RT-qPCR	Increase	Potential biomarker for LAC diagnosis; promote proliferation and metastasis	[71]
	hsa_circ_0012673	miR-22/ErbB3	RT-qPCR	Increase	Potential biomarker for LAC diagnosis; promote proliferation	[72]
Breast cancer	circRNA-000911	miR-449a/Notch1	Microarray analysis; RT-qPCR	Decrease	Promote apoptosis	[73]
	circ-ABCB10	miR-1271	Microarray analysis; RT-qPCR	Increase	Promote proliferation	[74]
	hsa_circ_0001982	miR-143	Microarray analysis; RT-qPCR	Increase	Promote proliferation	[75]
	circGFRA1	miR-34a	Microarray analysis; RT-qPCR	Increase	Promote proliferation	[76]
GC	hsa_circ_0074362	–	RT-qPCR	Decrease	Potential biomarker for GC diagnosis	[77]
	hsa_circ_002059	–	RT-qPCR	Decrease	Potential biomarker for GC diagnosis	[78]
	hsa_circ_0014717	–	Microarray analysis; RT-qPCR	Decrease	Potential biomarker for GC diagnosis	[79]
	hsa_circ_0000190	–	RT-qPCR	Decrease	Potential biomarker for GC diagnosis	[80]
	hsa_circ_0000520	–	Microarray analysis; RT-qPCR	Decrease	Potential biomarker for GC diagnosis	[81]
	hsa_circ_0001017 and hsa_circ_0061276	–	Microarray analysis; RT-qPCR; RT-ddPCR	Decrease	Potential biomarker for GC diagnosis	[82]
	hsa_circ_100269	miR-630	RT-qPCR	Decrease	Potential biomarker for GC diagnosis; repress proliferation	[83]
	circLARP4	miR-424–5p/LATS1	Microarray analysis; RT-qPCR	Decrease	Potential biomarker for GC prognosis; repress proliferation and invasion	[84]
HCC	hsa_circ_0001649	–	RT-qPCR	Decrease	Potential biomarker for HCC diagnosis	[85]
	hsa_circ_0005075	–	Microarray analysis; RT-qPCR	Increase	Potential biomarker for HCC diagnosis	[86]
	circZKSCAN1	–	RT-qPCR	Decrease	Potential biomarker for HCC diagnosis; repress proliferation, migration and invasion	[87]
	circMTO1	miR-9/p21	Microarray analysis; RT-qPCR	Decrease	Potential biomarker for HCC prognosis; repress proliferation and invasion	[88]
	cSMARCA5	miR-17–3p, miR-181b-5p/TIMP3	RNA-seq; RT-qPCR	Decrease	Potential biomarker for HCC prognosis; repress proliferation and migration	[89]
	circ_0067934	miR-1324/FZD5	RT-qPCR	Increase	Promote proliferation and migration	[90]
	circHIPK3	miR-124/AQP3	RT-qPCR	Increase	Promote proliferation and migration	[32]
	circRNA_100338	miR-141–3p	Microarray analysis; RT-qPCR	Increase	Promote migration and invasion	[91]
CRC	circRNA0003906	–	RT-qPCR	Decrease	Potential biomarker for CRC diagnosis	[92]
	hsa_circ_001988	–	RT-qPCR	Decrease	Potential biomarker for CRC diagnosis	[93]
	hsa_circ_103809 and hsa_circ_104700	–	Microarray analysis; RT-qPCR	Decrease	Potential biomarker for CRC diagnosis	[94]
	hsa_circ_0000069	–	Microarray analysis; RT-qPCR	Increase	Potential biomarker for CRC diagnosis; promote proliferation, migration and invasion	[95]
	hsa_circ_0007534	–	Microarray analysis; RT-qPCR	Increase	Potential biomarker for CRC diagnosis; promote proliferation	[96]
	hsa_circ_0020397	miR-138/TERT, PD-L1	RT-qPCR	Increase	Potential biomarker for CRC diagnosis; promote invasion	[97]
Bladder cancer	circTCF25	miR-103a-3p, miR-107/CDK6	Microarray analysis; RT-qPCR	Increase	Promote proliferation and migration	[98]
	circRNA-MYLK	miR-29a/VEGFA	Microarray analysis; RT-qPCR	Increase	Promote cancer proliferation	[99]
	circBCRC4	miR-101/EZH2	RT-qPCR	Decrease	Promote apoptosis	[100]
	circ-ITCH	miR-17, miR-224/p21, PTEN	RT-qPCR	Decrease	Repress proliferation and migration	[101]
Glioma	hsa_circ_0046701	miR-142–3p/ITGB8	RT-qPCR	Increase	Promote proliferation and invasion	[102]
	circ-FBXW7	–	RNA-seq; RT-qPCR	Decrease	Code protein	[28]
	circ-SHPRH	–	RNA-seq; RT-qPCR	Decrease	Code protein	[42]

CircRNA: Circular RNA; CRC: Colorectal cancer; GC: Gastric cancer; HCC: Hepatocellular carcinoma; LAC: Lung adenocarcinoma; NSCLC: Non-small-cell lung cancer; RT-ddPCR: Reverse transcription-droplet digital polymerase chain reaction; RT-qPCR: Reverse transcription-quantitative polymerase chain reaction.

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