Circular RNA: The evolving potential in the disease world

Table 1 Circular RNAs as potential biomarkers in major human diseases

Body system	Disease	circRNA	Expression	Ref.
Cardiovascular	Myocardial infarction	circRNA_081881	Down	[43]
		MICRA	Up
	Cardiac fibrosis	circRNA_010567	Up	[44]
	Congenital heart disease	hsa_circ_004183	Down	[45]
		hsa_circ_079265
		hsa_circ_105039
	Hypertension	hsa_circ_0037911	Up	[46]
	Cardiomyopathy	circDNAJC6	Down	[47]
		circTMEM56
		circMBOAT2
	Heart failure	hsa_circ_0062960	Up	[48]
	Coronary artery disease	hsa_circ_0124644	Down	[49]
		hsa_circ_0001879	Down	[50]
		hsa_circ_0004104	Down	[51]
		hsa_circ_0001445	Up
	Atrial fibrillation	hsa_circ_025016	Up	[52]
Central nervous system	Moyamoya disease	hsa_circRNA_089761	Down	[53]
		hsa_circRNA_100914
		hsa_circRNA_089763
	Temporal lobe epilepsy	circ-EFCAB2	Up	[54]
		circ-DROSHA	Down	[55]
		circRNA-0067835	Down
	Alzheimer’s disease	CDR1as/ciRS-7	Down	[56,57]
		circPVT1	Up	[58]
	Parkinson’s disease	CDR1as/ciRS-7	Up	[59]
		circzip-2
	Multiple sclerosis	circ_0005402	Down	[60]
		circ_0035560		[61]
	Prion disease	CDR1as/ciR-7	Up	[56,62]
Psychiatry	Schizophrenia	hsa_circRNA_104597	Down	[63]
Respiratory	Tuberculosis	hsa_circRNA_001937	Up	[64]
		hsa_circRNA_005086	Up	[35]
		hsa_circRNA_009024	Up
		hsa_circRNA_104964	Down
		hsa_circRNA_102101	Down
		hsa_circRNA_104296	Down
	Siliocosis	hsa_circ_0058493	Up	[65]
		circRNA-012091	Down	[66]
	Pulmonary hypertension	circ-GSAP	Down	[67]
		circ_0068481	Up	[68]
	Acute respiratory distress syndrome	hsa_circRNA_101952	Up	[69]
		hsa_circRNA_101523	Up
		hsa_circRNA_102927	Down
		hsa_circRNA_100562	Down
		hsa_circRNA_102034	Down
Endocrine	Diabetes mellitus	CiRS-7	Up	[70]
		hsa_circ_0068087		[71]
		hsa_circ_0124636		[71]
		hsa_circ_0139110
		hsa_circ_0054633
	Diabetes/glucose	CDR1as/cirRS-7	Up	[70,72]
	Homeostasis/CVD	circRNA-HIPK3	Up	[73]
		circRNA-WDR77	Up
		circANKRD36	Up
	Diabetic cardiomyopathy	circRNA_000203	Up	[74]
		circRNA_010567	Up	[44]
		hsa-circ-0076631	Up	[75]
	Diabetic nephropathy	circRNA_15698	Up	[59,75,76]
	Gestational diabetes	circ_5824	Down	[75]
		circ_3636	Down
		circ_0395	Down
	Diabetic retinopathy	circRNA-0005015	Up	[75]
		circRNA-HIPK3	Up	[77]
		cZNF609	Up	[78]
		circRNA-cPWWP2A	Up	[79]

Table 2 Circular RNAs as potential biomarkers in major human cancers

Cancer	circRNA	Expression	Function/target	Ref.
Lung cancer	hsa_circ_0005962	Up	Promotes proliferation; non-invasive diagnostic biomarker	[80]
	hsa_circ_0086414	Down	Cancer progression; non-invasive diagnostic biomarker	[80]
	hsa_circ_0102537	Down	Biomarker for diagnosis; fluid shear stress and PI3K-Akt signaling pathway	[81]
	hsa_circ_0000190	Up	Tumorigenesis and immune evasion; facilitates tumorigenesis and immune evasion by upregulating the Expression of soluble PD-L1 in non-small-cell lung cancer	[82]
	CDR1as	Up	Enduring growth signaling; regulating miR-219a-5p/SOX5 axis	[83]
	hsa_circ_0001715	Up	Distant metastasis; potential diagnostic and prognostic Biomarker	[84]
	circPTK2	Down	Activating invasion and metastasis; inhibits TGF-β-induced epithelial-mesenchymal transition and metastasis by controlling TIF1γ	[85]
	circ_0067934	Up	Activating invasion and metastasis; regulating miR-1182/KLF8 axis and activating Wnt/β-catenin pathway	[86]
	hsa_circ_0012673	Up	Cancer cell proliferation and invasion; via miR-320a/LIMK18521 axis	[87]
	F-circEA-2a	Up	Promotes cell migration and invasion	[88]
	F-circEA	Up	Promotes cell migration and invasion; potential diagnostic value	[89]
	circRNA_100876	Up	Distant metastasis; potential prognostic biomarker and therapeutic target	[90]
	circRNA_ZEB1/hsa_circ_0023404	Up	Promotes proliferation, migration, and invasion; regulating miR-217/ZEB1 axis	[91]
	CiRS-7	Up	Increased proliferation, migration, and invasion, yet reduced apoptosis; targets NF-κB signaling	[92]
HCC	has_circ_0001445	Up	Regulates proliferation and migration; targets miR-942-5p/ALX4 axis	[93]
	has_circ_0027089	Up	Biomarker for diagnosis of hepatitis-related HCC	[94]
	has_circ_0016788	Up	Evading growth inhibitors; targets miR-486/CDK4 pathway	[95]
	circ-SMARCA5	Down	Inhibits cell proliferation and promotes apoptosis; potential prediction and monitoring biomarker for HCC	[96]
	circSMAD2	Down	Activating invasion and metastasis; inhibits epithelial-mesenchymal transition by targeting miR-629	[97]
	has_circ_0064428	Down	Immune-associated prognostic biomarker for HCC patients	[98]
	has_circ_0009582; circ_0037120	Up	Biomarker for diagnosis	[99]
	has_circ_0140117	Up	Potential biomarkers for predicting occurrence of HCC	[99]
	CDR1as	Up	Cell proliferation and migration; enduring growth signaling	[100]
Gastric cancer	has_circ_0010882	Up	Role in proliferation, migration, and invasive phenotypes; regulation of PI3K/Akt/mTOR signaling	[101]
	has_circ_0001017	Down	Cell proliferation, migration, and invasion; sponge of miR-197	[102]
	has_circ_0061276; hsa_circ_0001017	Down	Potential prognostic tumor biomarkers	[103]
	has_circ_0000745	Down	Regulating GC growth and migration; promising diagnostic biomarker	[104]
	circ-Rangap1	Up	Cancer invasion and metastasis; targeting miR-877-3p	[105]
	has_circ_0000181	Up	Distant metastasis and TNM stage; diagnostic biomarker	[106]
	circ-PSMC3	Down	Cell proliferation and metastasis	[107]
	circ-LMTK2	Down
	circ-DLST	Up
	circ-KIAA1244	Down	TNM stage and lymphatic metastasis	[108]
	circ-ZFR	Down	Evading growth inhibitors; sponging miR-130a/miR-107 and modulating PTEN	[109]
	CDR1as	Down	Evading growth inhibitors; targeting miR-876-5p/GNG7 axis	[110]
	circRNA-000425	Down	Evading growth inhibitors; proliferation, apoptosis, and cell drug sensitivity via YAP1-induced tumorigenesis	[111]
	circRNA_0023642	Up	Activating invasion and metastasis; regulating epithelial-mesenchymal transition	[112]
	has_circ_0001178	Up	Invasion and metastasis; via sponging multiple miRNAs	[113]
	has_circ_0005927	Down	Cell colony-forming ability, migration, and invasion; regulating miR-942-5p/BATF2 axis	[114]
	has_circ_0082182	Up	Drug resistance and cancer progression; sponging miR-326	[115]
	hsa_circ_0082182, hsa_circ_0000370	Up	Inhibit apoptosis; potential diagnostic markers	[116]
	has_circ_0035445	Up	Promotes proliferation and migration but suppresses apoptosis; potential diagnostic marker	[116]
	has_circ_0006990	Up	Cancer progression; via mediation of hsa_circ_0006990/miR-132-3p/MUC13 axis	[117]
	CDR1as	Up	Enduring growth signaling; regulating microRNA-7	[118]
	circHIPK3	Up	Enduring growth signaling; sponging miR-7	[119]
	hsa_circ_0007534	Up	Blocking apoptosis	[120]
	hsa_circRNA_103809	Down	Cell proliferation and migration; via miR-532-3p/FOXO4 axis	[121]
	hsa-circ-0020397	Up	Regulates CRC cell viability, apoptosis, and invasion by promoting the expression of miR-138 target genes	[121]
Breast cancer	hsa_circ_0001785	Up	Proliferation, migration, and invasion; potential diagnostic value	[122]
	hsa_circ_0008673	Up	Prognostic predictor of OS and DSS	[122]
	circ-ITCH	Down	Evading growth inhibitors; targets Wnt/β-catenin pathway	[123]
	hsa_circ_0104824	Down	Cell migration, cell-cell adhesion, and proliferation; promising predictive biomarker and therapeutic target	[124]
Esophageal cancer	circ-TTC17	Up	Promotes proliferation and migration; novel biomarker for diagnosis, treatment, and prognosis	[125]
	hsa_circ_0007203 (circ-DLG1)	Up	Promotes cell proliferation	[126]
	hsa_circ_0004771	Up	Diagnostic biomarker; targets via miR-339-5p/CDC25A axis	[127]
	circGSK3β	Up	Promoting metastasis; augmenting β-catenin signaling	[128]
	circ-SLC7A5	Up	Regulator of tumorigenesis and metastasis	[129]
Pancreatic cancer	circ-LDLRAD3	Up	Proliferation, migration and invasion; via miR-137-3p/PTN axis	[130,131]
	circNFIB1, hsa_circ_0086375	Down	Lymphangiogenesis and lymphatic metastasis; via miR-486-5p/PIK3R1/VEGF-C axis	[132]
Thyroid cancer	has_circ_0124055	Up	Regulates proliferation and apoptosis: Prognostic and diagnostic indicator	[133]
	has_circ_0101622	Up	Regulates proliferation and apoptosis: Prognostic and diagnostic indicator	[133]
Gallbladder cancer	circ-MTO1	Up	Early diagnostic and prognostic marker	[134]
	circHIPK3	Up	Evading growth inhibitors; sponging miR-124	[135]
Ovarian/endometrial cancer	has_circ_0078607	Up	Adverse prognostic indicator for ovarian cancer; regulating miR-32-5p/SIK1 network	[136]
	has_circ_0061140	Up	Activating invasion and metastasis; targeting miR-197/high mobility group protein A1 axis in endometrial cancer	[137]
Glioma/glioblastoma	hsa_circ_0046701	Up	Enduring growth signaling; critical regulatory roles via hsa_circ_0046701/miR-142-3p/ITGB8 axis	[138]
	circ-FBXW7	Down	Enduring growth signaling; potential prognostic implications	[139]
	circNFIX	Up	Blocking apoptosis; regulating miR-378e/RPN2 axis	[140]
	cZNF292	Up	Promoting angiogenesis; Wnt/β-catenin signaling	[141]

HCC: Hepatocellular carcinoma; OS: Overall survival; DSS: Disease-specific survival; TGF-β: Transforming growth factor-β; GC: Gastric cancer; circRNA: Circular RNAs.

Table 3 Genome-wide identification of circular RNAs: How it began

Ref.	Genome-wide identification of circRNAs
Salzman et al[18], 2012	Aimed to distinguish cancer-specific exon scrambling events
	Identified 2748 scrambled isoforms in Hela and H9 embryonic stem cells
	Conclusion: 98% of scrambled isoforms represent circRNAs
Jeck et al[8], 2013	Classified circular transcripts based on their levels of abundance using three stringencies categories (low, medium, high)
	Conclusion: circRNAs are conserved, stable, and nonrandom products of RNA splicing that could be involved in the control of gene expression
Memczak et al[7], 2013	Developed a computational method to detect circRNAs
	Conclusion: circRNAs form a significant class of post-transcriptional regulators
Guo et al[19], 2014	Identified and quantified human circRNAs from ENCODE Ribozero RNA-seq data
	Conclusion: Most circRNAs are nonsignificant side-products of splicing error
Zhang et al[20], 2014	Developed CIRCexplorer to distinguish thousands of circRNAs in humans with p(A)-wloRNase R RNA-seq data
	Conclusion: Alternative circularization paired with alternative splicing can generate additional circRNAs from one gene, which is suggestive of the new line of complexity in gene regulation

circRNA: Circular RNAs.