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Abstract

Circular RNAs (circRNAs), which were discovered as a special class of endogenous non-coding RNAs, have recently shown huge capabilities as gene regulators in different species in a wide variety of organisms including viruses, plants, archaea and animals. These circRNAs mainly arise from exons or introns in different combinations by special selective splicing and are enriched in cytoplasm. Apart from that, circRNAs usually display patterns of cell-type, tissue-type and developmental-stage specific expression in eukaryotic transcriptome. These findings hint at the vital function of circRNAs in development and diseases. Herein, we summarize the current understanding of the molecular characteristics of circRNAs and discuss their proposed functions and mechanism-of-action in human diseases, animals as well as botanics.

Keywords

Circular RNA anti-cancer diagnosis botanics animals

1. Introduction

Circular RNAs (circRNAs), a new group of endogenous non-coding RNAs, were identified in the early 1990s as transcripts with scrambled exon order and continued to be reported about their structure, mechanism and function and getting the research hotspots over the following two decades [1, 2]. Different from the traditional linear RNAs that are terminated with 5’caps and 3’tails, circRNAs form their special closed loop structures lack of the 5’ end cap and the 3’ end of poly (A) tail [3]. Compared with microRNAs (miRNAs) and long, non-coding, RNAs (lncRNAs), circRNAs have a higher degree of stability and sequence conservation among mammalian cells because of their nuclease resistance properties [4, 5].

Recently, a plethora of studies reported the expression of a variety of circRNAs in different species ranging from humans and animals to botanics [6, 7, 8]. These studies demonstrate that circRNAs are evolutionarily conserved and expressed in a time, cell type and gene-specific manner. Owing to the rapid development of bioinformatics analysis programs and high-throughput sequencing technology, researchers have discovered thousands of circRNAs and found that they may be involved in atherosclerotic vascular diseases, neurological disorders, carcinomas and other diseases [9, 10, 11]. In-depth study of the structure and function of circRNAs can be better to understand the mechanism of diseases, improve the level of diagnosis and prevention of related diseases.

Figure 1.

Possible action mechanisms of circRNAs. Spliced from DNA, CircRNAs function as competing endogenous RNAs or miRNA sponges to influence the posttranscriptional actions of miRNAs. CircRNAs can also be a temple for protein translating mediated by the IRES, and modulate the downstream gene activity by combing RBPs.

1.1 The regulatory role of circRNAs

Recent studies have revealed that circRNAs are involved in a wide range of life processes as well as in much human pathology. It has been suggested circRNAs play a crucial role in gene regulation at the post-transcription or transcription level and then have an impact at the level of gene expression [12] (Fig. 1). Although functions of a few circRNAs have been demonstrated, the full aspect of functions for these molecules is still unclear.

1.2 CircRNAs function as miRNAs sponges

There is a hypothesis known as ceRNA (competing endogenous RNA) showing that RNAs including mRNAs, pseudogene and lncRNAs compete for miRNA binding using the same microRNA response elements (MREs) to regulate each other and the downstream genes [13]. In recent years, a number of studies have suggested that circRNAs, miRNAs and their downstream mRNAs can form “circRNA-miRNA-mRNA” regulatory network, which means that circRNAs could act as miRNAs sponges or called miRNAs reservoir. Thomas and his colleagues recently uncovered the function of one such circRNA named ciRS-7, produced from the cerebellum degeneration-related protein 1 antisense (CDR1), acted as an endogenous miR-7 inhibitor and weakened the regulatory effects of miR-7 on target mRNAs [14]. The ciRS-7/miR-7 interaction was tightly associated with the development of cancers including astrocytoma, neuroblastoma, and lung carcinoma [15]. As a result, the circ-miRNA axis, irrespective of promotion or suppression, has significant effects on various pathways in human diseases and is worthy more thorough study.

1.3 CircRNAs interact with RNA-binding proteins

CircRNAs can bind directly to RNA-binding proteins (RBPs), or indirectly correlate with RBPs to form large RNA-protein complexes (RPCs) [16]. These RPCs can regulate the pool of RBPs or small RNAs capable of interacting with the canonical linear RNA counterpart [17]. It has been shown that the circular Mbl (circMbl) can bind MBL while MBL can in turn regulate the formation of circMbl, suggesting an existence of a sophisticated autoregulatory mechanism to fine-tune the production and availability of the protein [16]. Moreover, the circRNA circ-Foxo3 has been found to regulate the cell cycle progression by binding CDK2 and P21 proteins, resulting in the formation of a ternary complex that inhibits cell cycle progression and cell proliferation [18]. Their special loop structures can make them efficiently avoid degradation from RNA termini, growing evidence has proved the important role of circRNAs played in RNA transcription.

1.4 CircRNAs are involved in the regulation of gene transcription

Despite the fact that most circRNAs are cytoplasmatic, some circular isoforms can be detected in the nucleus as well. Zhang et al. found knockdown of ci-ankrd52 caused a significant downregulation of the linear mRNA ankrd52, but had no effects on upstream or downstream genes. Subsequently, they found an interaction between circRNAs and the elongation complex of Pol II, suggesting a potential mechanism of these circRNAs in regulating gene transcription [19].

1.5 Few circRNAs could be translated

The fact that most circRNAs are derived from protein-coding sequences, carry open reading frames (ORFs), and are located in the cytoplasm raises the question that some of them might be able to translate into proteins. Recent research reported that engineered circRNAs that were inserted an internal ribosome entry sites (IRESs) in upstream of the start codons of a protein could be translated in vitro or in vivo. It has been shown that 34% of the single circular exon contain the start codon in human fibroblasts, suggesting a widespread role of circRNAs as mRNA traps [20]. For example, circ-ZNF609 can be translated into a protein in a way of splicing-dependent and cap-independent in vitro differentiation of murine and human myoblasts [21]. In addition, other studies have shown that synthesised circular RNAs with multiple FLAG-coding sequences could also be translated into proteins by mechanism similar to rolling circle amplification in absence of internal ribosome entry sites [22]. Zhang et al. provided the first translational evidence of a cancer-associated circular RNA, a novel tumor suppressor protein SHPRH-146aa produced by IREs-driven circ-SHPRH. It was found that the novel tumor suppressor protein produced by a circular RNA acts synergistically with the full-length protein to reduce degradation as a protective decoy molecule, thereby increasing the tumor suppressor function of the gene. Prolonged patient survival was observed in glioblastoma patients with elevated levels of SHPRH-146aa [23]. This study marks the discovery of the first circular RNA with overlapping start and stop codons, resulting in translation of the complete circRNA, exploring mechanisms not previously discovered or seen.

Table 1
Summary circRNAs acting as miRNAs sponges in non-cancer diseases

Sequence name	Non-tumor diseases	Expression	miRNA	Function and	First	Year	Country	Reference
		level of	sponge	target protein	author
		circRNA
ciRS-7 Or CDR1as	Alzheimer’s disease	$\uparrow$	miR-7	UBE2A	Y. Zhao	2016	USA	[24]
ciRS-7 Or CDR1as	Parkinson’s disease	$\uparrow$	miR-7	$\alpha$ -synuclein/EGFR/SNCA/IRS	T.B. Hansen	2013	Denmark	[14]
circRar1	Lead-inducedneuronal cell	$\uparrow$	miR-671	Akt/Caspase-8	A. Nan	2017	China	[44]
ciRS-7 Or CDR1AS	Diabetes	$\uparrow$	miR-7	Myrip/Pax6	H. Xu	2015	China	[33]
circHIPK3	Diabetic retinopathy	$\uparrow$	miR-30a-3p	VEGF-C/FZD4/ WNT2	K. Shan	2017	China	[45]
circRNA_CER	Osteoarthritis	$\downarrow$	miR-136	MMP13	Q. Liu	2016	China	[46]
hsa_circ_0005105	Osteoarthritis	$\uparrow$	miR-26a	NAMPT	Y. Wu	2017	China	[47]
hsa_circ_0045714	Osteoarthritis	$\uparrow$	miR-193b	IGF1R	B.F. Li	2017	China	[48]
circRNA_ZNF609	Hirschsprung’s disease	$\downarrow$	miR-150-5p	AKT3	L. Peng	2016	China	[49]
circRNA_0046367	Hepatic steatosis	$\downarrow$	miR-34a	PPAR $\alpha$	X.Y. Guo	2017	China	[50]
circRNA_000203	Cardiac fibroblasts	$\uparrow$	miR-26b-5p	Colla2/CTGF	C.M. Tang	2017	China	[35]
mmu_circRNA_0000254 (HRCR)	Heart failure	$\downarrow$	miR-223	ARC	K. Wang	2016	China	[51]
ciRS-7 Or CDR1as	Myocardial infarction	$\uparrow$	miR-7a	PARP/SP1	H.H. Geng	2016	China	[52]
mmu_circRNA_010567	Myocardial fibrosis	$\uparrow$	miR-141	TGF- $\beta$ 1	B. Zhou	2017	China	[53]
has_circ_000595	Aortic aneurysm	$\uparrow$	miR-19a	COX-2 and NF- $\kappa$ B	C. Zheng	2015	China	[54]
circRNA_101238	Thoracic aorticdissection	$\uparrow$	miR-320a	MMP9	M. Zou	2017	China	[55]
circRNA_081881	Acute myocardialinfarction	$\uparrow$	miR-548	PPAR $\gamma$	Y.Y. Deng	2016	China	[56]
circMFACR	Myocardial infarction	$\uparrow$	miR-652-3p	MTP18	K. Wang	2017	China	[57]
circWDR77	Vascular smoothmuscle cells (diabetesmellitus correlated vasculopathy)	$\uparrow$	miR-124	FGF2	J. Chen	2017	China	[58]
has_circ_0010729	Angiogenesis	$\uparrow$	miR-186	HIF-1 $\alpha$	R.Y. Dang	2017	China	[59]

$\downarrow$ means down-regulated, $\uparrow$ means up-regulated.

2. CircRNAs and human diseases

2.1 CircRNAs and non-cancer diseases: Novel rising stars

Recent works have suggested that circRNAs may play important roles in the initiation and development of numerous human diseases such as central nervous system diseases, cardiovascular diseases, osteoarthritis and so on and could potentially become new biomarkers of diseases. In different diseases, circRNAs play their different roles and sometimes the mechanism of action of circRNAs in different diseases could be same. With regard to their function, several studies reported that circRNAs mainly serve as miRNA sponges to regulate gene expression. Therefore, miRNAs interacting with circRNAs and target mRNAs have been listed out in this review (Table 1).

In central nervous system diseases, it has been found that ciRS-7 or CDR1as acts as mi-7 sponge in Alzheimer’s disease (AD) [24] and Parkinson’s disease (PD) [14]. Recent studies investigated that in the HT22 cells with oxygen-glucose deprivation/reoxygenation (OGD/R), the expression of mmu-circRNA-015947 is up-regulated in cerebral ischemia-reperfusion injury (IRI), and could interact with miRNAs (mmu-miR-3057-3p, mmu-miR-329-5p, mmu-miR-5098, mmu-miR-188-3p and mmu-miR-683) using the bioinformatics analysis and their idiographic action mechanism is to be addressed [25].

Cardiovascular diseases (CVD) represent the predominant cause of morbidity and mortality worldwide, although the age-standardized mortality from CVD has been halved by better prevention and wider use of appropriate treatments for acute events [26]. Numerous studies have confirmed that miRNAs are closely related to cardiovascular diseases, which are potential emerging biomarkers with extreme sensitivity for early diagnosis and novel treatment for CVD [27]. Therefore, as a kind of miRNA sponge, circRNAs contain complementary binding sites, which can “sponge up” miRNAs of a particular family and serve as competitive inhibitors that suppress the ability of the miRNAs to bind with their mRNA targets [17]. For example, SRY (sex-determining region Y), one circRNA, contains 16 miRNA-138 binding sites. He et al. confirmed that miR-138 protects cardiomyocytes from hypoxia-induced apoptosis, which is mediated mainly via MLK3/JNK/c-jun signaling pathway [14, 28]. In addition, this research can also infer that SRY may aggravate hypoxia-induced cardiomyocytes apoptosis. In vitro and in vivo approaches, circ-Foxo3 was found highly expressed in heart samples of aged patients and mice, and it has proved that the roles of circ-Foxo3 in cellular senescence are clear via interacting with protein ID-1, E2F1, FAK, and HIF1 $\alpha$ [29]. It has also found other circRNAs like circRNA cZNF292 which exhibits proangiogenic activities in vitro [30], circRNA_ANRIL which induces nucleolar stress and p53 activation, resulting in the induction of apoptosis and inhibition of proliferation in atherosclerosis [31] and hsa_circ_0124644 which can be used as a diagnostic biomarker of coronary artery disease [32]. However, the current studies of circRNAs on CVD are relatively fragmented. The relationship between circRNAs and CVD needs further investigation. But I believe that circRNAs will gradually become one of the most noticeable areas in the field of CVD and become novel diagnostic biomarkers and new therapeutic interventions for CVD in the soon future.

As one of the most studied and classical circRNA, ciRS-7 or CDR1as and the Cdr1as/miR-7 pathway also participate in regulating insulin granule secretion. The Cdr1as/miR-7 pathway acts on target Myrip and target Pax6 that enhances insulin transcription, thereby activating or inhibiting insulin secretion related signaling pathways. That provides a new idea for the treatment and research of diabetes [33]. The microarray analysis [34] hints that hsa_circ_0054633 could serve as a novel potential biomarker for pre-diabetes and T2DM. In the diabetic mouse myocardium, circRNA_000203 was shown upregulated and the pro-fibrosis effect of it is revealed [35].

Similarly, circRNAs are also found to play their in role in gynecological disease [36]. The different expression of circular RNAs in the placental tissues of pregnant women with preeclampsia were explored. The result revealed that many circRNAs were differentially expressed in placental tissues with preeclampsia versus their controls. Among them, 143 circRNAs were up-regulated and 158 were down-regulated. Finally, this research performed a literature comparison to forecast the possible mechanisms of circRNA function during preeclampsia and predicted circRNAs may contribute to the pathogenesis of preeclampsia by acting as miRNA sponges. Circ_101222 is significantly higher expression and could interact with miR-181 because of its role in preeclampsia by using the bioinformatics analysis and that make it a possible a diagnostic marker [37].

CircRNAs are also found in the study of other diseases. Cui and his colleagues performed a study to determine whether circRNA molecules in peripheral blood mononuclear cells (PBMCs) could be used as novel non-invasive biomarkers for major depressive disorder (MDD) and discovered that altered expression of hsa_circRNA_103636 in PBMCs is a potential novel biomarker for the diagnosis and treatment of MDD [38]. CircRNA_100783 [39] were found that the expression level is up-regulated in ageing human CD8(+) T cell populations and the accompanying loss of CD28 expression and might be involved in the longitudinal tracking of CD28-related CD8(+) T cell ageing and global immunosenescence. Meanwhile, more circRNA microarray analysis reveals circRNAs’ role in Moyamoya disease [40], rheumatoid arthritis [41], infantile hemangioma [42], and intervertebral disc degeneration (IDD) [43] and so on. And also find some circRNAs as promising diagnostic biomarker for these diseases.

Table 2
Summary of the expression of circRNAs acting as miRNA sponge in carcinomas

Sequence name	Tumor diseases	Expression	miRNA	Function and	First	Year	Country	Reference
		level	sponge	target protein	author
circHIAT1	Clear cell renal cellcarcinoma (ccRCC)	$\downarrow$	miR-195-5p/29a-3p/29c-3p	CDC42	K. Wang	2017	China	[71]
circRNA_TCF25	Bladder carcinoma	$\uparrow$	miR-103a-3p,miR-107	CDK6	Z. Zhong	2016	China	[72]
circRNA_MYLK	Bladder carcinoma	$\uparrow$	miR-29a-3p	VEGFA/VEGFR2	Z. Zhong	2017	China	[73]
circHIPK3	Bladder carcinoma	$\downarrow$	miR-558	HPSE	Y. Li	2017	China	[74]
circRNA_100290	Oral cancer	$\uparrow$	miR-29	CDK6	L. Chen	2017	China	[75]
circRNA_Cdr1	Hepatoma carcinoma(HCC)	$\uparrow$	miR-7	CCNE1, PIK3CD	L. Yu	2016	China	[76]
circRNA_0005075	HCC	$\uparrow$	miR-23B-5P/93-3P/581/23A-5P	Biological process ofcell adhesion	X. Shang	2016	China	[77]
circRNA_ciRS-7	MVI in HCC	$\downarrow$	miR-7-	PIK3CD/p70S6K	L. Xu	2016	China	[78]
circRNA MTO1	HCC	$\downarrow$	miR-9	p21	D. Han	2017	China	[79]
circRNA-100338	Hepatitis B-relatedHCC	$\uparrow$	miR-141-3p	regulation of invasive potential	X.Y. Huang		China	[80]
circRNA_001569	Colorectal cancer	$\uparrow$	miR-145	E2F5/BAG4/ FMNL2	H. Xie	2016	China	[81]
circRNA_ITCH	Colorectal cancer	$\downarrow$	mir-7/mir-20a	Wnt/ $\beta$ -catenin	G. Huang	2015	China	[82]
circRNA_ciRS-7	Colorectal cancer	$\uparrow$	miR-7	EGFR/RAF	W. Weng	2017	China	[83]
has_circ_0020397	Colorectal cancer	$\uparrow$	miR-138	TERT/PD-L1	X.L. Zhang	2017	China	[84]
circRNA_ITCH	ESCC (esophagealsquamous cell cancer)	$\downarrow$	miR7/17/214-	ITCH phosphorylated DV12	F. Li	2015	China	[85]
circLARP4	Gastric cancer	$\downarrow$	miR-424-5p	LATS1	J. Zhang	2017	China	[86]
circPVT1	Gastric cancer	$\uparrow$	miR-125	ERF2	J. Chen	2017	China	[87]
circRNA_ITCH	Lung cancer	$\downarrow$	miR-7/miR-214	ICTH/Wnt/ $\beta$ -catenin	L. Wan	2016	China	[88]
circRNA_0013958	Lung adenocarcinoma	$\uparrow$	miR-134	Cyclin D1	X. Zhu	2017	China	[89]
circHIPK3	Non-small cell lungcancer (NSCLC)	$\uparrow$	miR-379	IGF1	F. Tian	2017	China	[90]
circRNA_UBAP2	Osteosarcoma	$\uparrow$	miR-143	Bcl-2	H. Zhang	2017	China	[91]
hsa_circ_0009910	Osteosarcoma	$\uparrow$	miR-449a	IL6R	N. Deng	2017	China	[92]
circGFRA1	Triple negative breastcancer (TNBC)	$\uparrow$	miR-34a	GFRA1	R. He	2017	China	[93]
circ_0006528	breast cancerchemoresistance	$\uparrow$	miR-7-5p	Raf1	D. Gao	2017	China	[94]
hsa_circRNA_100395	Papillary thyroidcarcinoma (PTC)	$\downarrow$	miR-141-3p/miR-200a-3p	E2F3, GLS, CCND2, PTEN, CCNG1,CDC25B andZFPM2	N. Peng	2017	China	[66]
circRNA_100284	Keratinocyte (HaCaT)cells	$\uparrow$	miR-217	EZH2	J. Xue	2017	China	[95]
circ-TTBK2	Neuroglioma	$\uparrow$	miR-217	HNF1 $\beta$ /Derlin-1	J. Zheng	2017	China	[67]

$\downarrow$ means down-regulated, $\uparrow$ means up-regulated.

Table 3

CircRNAs as a promising diagnostic biomarker for cancer

Sequence name	Samples	Tumor diseases	Expression	Reference
			level
has_circ_0035381	tissue	CSCC (Cutaneous squamous cell carcinoma)	$\uparrow$	[96]
has_circ_0022383	tissue	CSCC	$\downarrow$	[96]
circBRAF	tissue	Neuroglioma	$\downarrow$	[70]
hsa_circ_0067934	tissue and cell	ESCC	$\uparrow$	[97]
has_circ_002059	tissue, plasma	Gastric cancer	$\downarrow$	[98]
has_circ_001895	tissue	Gastric cancer	$\downarrow$	[99]
has_circ_0014717	tissue	Gastric cancer	$\downarrow$	[100]
has_circ_0000096	tissue and cell	Gastric cancer	$\downarrow$	[101]
has_circ_0000190	tissue	Gastric cancer	$\downarrow$	[102]
has_circ_0006633	tissues, plasma and cell	Gastric cancer	$\downarrow$	[103]
has_circ_0003159	tissue	Gastric cancer	$\downarrow$	[104]
hsa_circ_0001017	plasma	Gastric cancer	$\downarrow$	[64]
hsa_circ_0061276	plasma	Gastric cancer	$\downarrow$	[64]
hsa_circ_0000520	tissues, plasma and cell	Gastric cancer	$\downarrow$	[105]
hsa_circ_0000745	tissue, plasma	Gastric cancer	$\downarrow$	[106]
has_circ_0001649	tissue, serum	Gastric cancer	$\downarrow$	[107]
hsa_circ_0047905, hsa_circ_0138960	tissue	Gastric cancer	$\uparrow$	[108]
and has-circRNA7690-15
has_circ_001988	tissue	Colorectal cancer	$\downarrow$	[109]
has_circ_0007374	tissue, sell	Colorectal cancer	$\uparrow$	[110]
has_circ_0006229	tissue, sell	Colorectal cancer	$\downarrow$	[110]
circCCDC66	tissue	Colorectal cancer	$\uparrow$	[111]
circ-BANP	tissue	Colorectal cancer	$\uparrow$	[112]
has_circ_103809 and has_circ_104700	tissue	Colorectal cancer	$\downarrow$	[113]
has_circ_0000069	tissue and cell	Colorectal cancer	$\uparrow$	[114]
has_circ_0001649	tissue	HCC	$\downarrow$	[115]
has_circ_0004018	tissue	HCC	$\downarrow$	[65]
hsa_circ_0003570	tissue and cell	HCC	$\downarrow$	[116]
circ-ITCH	tisscu	HCC	$\downarrow$	[117]
circ_ZKSCAN1	tissues and cell	HCC	$\downarrow$	[118]
has_circ_104912	tissue	LSCC (Laryngeal squamous cell cancer)	$\downarrow$	[61]
has_circ_100855	tissue	LSCC	$\uparrow$	[61]
hsa_circ_0001982	tissue	Breast Cancer	$\uparrow$	[119]
circ-ABCB10	tissue	Breast Cancer	$\uparrow$	[120]
hsa_circ_0001785	plasma	Breast Cancer	$\downarrow$	[121]
hsa_circ_0004277	Bone marrow samples	Acute myeloid leukemia (AML)	$\downarrow$	[122]
hsa_circ_100876	tissue	Non-small cell lung cancer (NSCLC)	$\uparrow$	[123]
hsa_circRNA_103801	cell lines and tissues	Osteosarcoma (OS)	$\uparrow$	[124]
hsa_circRNA_104980	cell lines and tissues	OS	$\downarrow$	[124]
cir-GLI2	tissue	OS	$\uparrow$	[125]
hsa_circ_0001564	tissue	OS	$\uparrow$	[126]

$\downarrow$ means down-regulated, $\uparrow$ means up-regulated.

2.2 CircRNAs and carcinomas: Common molecules with huge potentials

Growing evidence shows that circRNAs have critical functions in tumor and serve as the huge diagnostic and therapeutic potentials for cancer. Compared with linear miRNA sponges, circRNAs have more miRNA binding sites, more stable structure and higher expression levels, and may be more effective in sequestering miRNAs and become a new target of non-coding RNA (ncRNA) regulation.

Technology circRNAs microarray analysis has been applied to many tumors including digestive system neoplasms, nervous system tumors, urinary system cancer, head and neck cancer and so on, such as hypopharyngeal squamous cell carcinoma (HSCC) [60], laryngeal squamous cell cancer tissues (LSCC) [61], basal cell carcinoma [62], Pancreatic ductal adenocarcinoma(PDAC) [63], gastric cancer [64], hepatocellular carcinoma (HCC) [65], papillary thyroid carcinoma (PTC) [66]. Some action mechanisms of circRNAs in physiological and pathological processes of human cancers has been well revealed especially acting as miRNAs sponges or other of involvement of signaling pathways in tumorigenesis based on the existing researches (Table 2). CircRNAs researches on neuroglioma found that circRNAs play different role in the tumorigenesis. CircTTBK2 is upregulated in glioma tissues and circTTBK2-miR-217-HNF1 $\beta$ /Derlin-1 axis plays oncogenic role in glioma cells. CircTTBK2 acts as a sponge of miR-217 to decrease miR-217 expression and promotes glioma cell proliferation, migration, and invasion, while inhibited apoptosis [67]. CircRNA cZNF292 plays its role via another mechanism. CircRNA cZNF292 regulates genes such as PRR11, Cyclin A, p-CDK2, VEGFR-1/2, p-VEGFR-1/2 and EGFR to inhibite glioma cell proliferation and cell cycle progression via Wnt/ $\beta$ -catenin signaling pathway [68]. As a another important circular oncogenic RNA, circ-FBXW7 can be a temple for protein translating and encode a protein termed FBXW7-185aa which regulates the stability of c-Myc together with protein FBXW7 encoded by maternal gene and inhibits the progression of glioma [69]. These findings reveal different action mechanism of circRNAs.

Meanwhile some circRNAs are just found abnormal expression level in tissues or blood and their clinical significance in human cancers which makes them a promising diagnostic biomarker for cancer screening and prognostic evaluation, but their specific action mechanisms are not characterized (Table 3). For example, a novel circRNA termed hsa_circ_0067934 was confirmed significantly overexpressed in ESCC tissues compared with paired adjacent normal tissues and high expression level of hsa_circ_0067934 was associated with poor differentiation, I–II T stage, and I–II TNM stage. Silence of hsa_circ_0067934 in vitro inhibits migration and proliferation of ESCC cells and blocks cell cycle progression, suggesting that hsa_circ_0067934 represents a novel potential biomarker for the treatment of ESCC [97]. Yao et al. reported that the expression level of circRNA_100876 in non small cell lung cancer (NSCLC) tissues was significantly elevated when compared with their adjacent nontumorous tissues. Moreover, there was a close correlation between the circRNA_100876 up-regulation expression and lymph node metastasis and tumor staging in NSCLC. In addition, Kaplan-Meier survival analysis demonstrated that the overall survival time of NSCLC patients with high circRNA_100876 expression was significantly shorter than those patients with low circRNA_100876 expression. In conclusion, these findings indicate that circRNA_100876 is closely related to the carcinogenesis of NSCLC and it might be served as a potential prognostic biomarker and therapeutic target for NSCLC [127]. In the future, functional consequences of circRNAs still need more researches and new technologies including Gene Oncology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and other databases which could be performed to investigate the functions of their target genes or signaling pathway.

Table 4
circRNAs databases

Databases	Main content	Adress	Reference
CSCD	cancer-specific circRNA	http://gb.whu.edu.cn/CSCD	[142]
exoRBase	embodys mRNA, lncRNA and circRNA in human blood exosomes	http://www.exoRBase.org	[143]
circRNADb	circRNAs that can encode proteins	http://reprod.njmu.edu.cn/circrnadb	[144]
CircNet	integrate circRNA-miRNA-mRNA’s interaction network	http://circnet.mbc.nctu.edu.tw/	[145]
circBase	CircRNAs collecte 6 species	http://www.circbase.org	[146]
circRNABase	interaction networks among ncRNAs and proteins	http://starbase.sysu.edu.cn/mirCircRNA.php	[147]
CircInteractome	explore circRNAs with interacting proteins and miRNAs	http://circinteractome.nia.nih.gov/	[148]
deepbase	expression, evolution and function of ncRNAs	http://deepbase.sysu.edu.cn/	[149]
CIRCpedia	the identified alternative back-splicing and alternativesplicing in circRNAs	http://www.picb.ac.cn/rnomics/circpedia/	[150]
TSCD	circRNAs in human and mouse	http://gb.whu.edu.cn/TSCD	[151]
Circ2Traits	circular RNA potentially associated with disease andtraits	http://gyanxet-beta.com/circdb/	[152]
RegRNA	identifying regulatory RNA motifs and elements	http://regrna.mbc.nctu.edu.tw/php/prediction.php	[153]
AtCircDB	circular RNAs in Arabidopsis	http://genome.sdau.edu.cn/circRNA	[138]

3. CircRNAs and animals

Thousands of eukaryotic protein-coding genes are not canonically spliced to produce circular RNAs not only in human but also in animals. In fact, ciRS-7, as the most classical and most studied cricRNA, is found predominantly in human, zebrafish and mouse brain. Then more animal models of research ciRS-7, or ciRS-7-miR-7-target gene axis in human diseases are established. Zebrafish is the most common animal experimental model. Therefore, with no doubt, researchers sequenced circRNAs in zebrafish and identified 3868 circRNAs using three algorithms and show that some circRNAs may function as miRNA sponges. In addition, they investigated the existence of reverse complementary sequences in the flanking regions of only 25 exonic circRNAs, indicating that the mechanism of zebrafish exonic circRNA biogenesis might be different from that in mammals. Moreover, 1122 zebrafish circRNA sequences showed homology with the circRNAs of human, mouse and coelacanth [128].

Avian leukosis virus subgroup (ALV-J) is an oncogenic neoplasm-inducing retrovirus that causes significant economic losses in the poultry industry. In Zhang’s study, 1800 circRNAs were detected by circRNA sequencing of liver tissues from ALV-J-resistant and ALV-J-susceptible chickens and 32 differentially expressed circRNAs were selected for analyzing. This study provides the first evidence that circRNA alterations are involved in resistance to ALV-J-induced tumor formation and proposes that circRNAs may help to mediate tumor induction and development in chickens [129].

CircLMO7 may function as a competing endogenous RNA for miR-378a-3p [130], and circFUT10 [131] directly bind to miR-133a to regulated myoblasts differentiation and cell survival in cattle. RNA-seq showed that the expression of circRNA showed a dynamic change with the development process.

3.1 Expression of circRNAs in plants

Actually, when scientist researched the spindle tuber disease of potato, the term “viroid” were first found as single stranded, circular and non-coding pathogenic RNAs that can infect higher plants [132]. It is the first time that a circular RNA was found. With the deepening of the researchers on circRNAs research, more cirRNAs are proved to be important in the mechanism of plant development and pathogenesis.

When researchers focus on ethylene pathway in tomato fruit, a new perspective of the roles of circRNAs were elucidated [133]. A large number of circRNAs and target genes are found and thus set up a sophisticated regulatory model consisting of circRNAs, target genes and ethylene. More researches are needed to reveal the role of circRNAs which could act as potential miRNAs sponges. Besides, identification of circular RNAs in soybean [134], leaves during the Lifespan of Arabidopsis [135], polyploid Gossypium species [136] and Arabidopsis thaliana [137] has been completed preliminary. These analyses revealed the prevalence of circRNAs in plants and provide new biological insights into plant circRNAs. Because of the well research on Arabidopsis, AtCircDB has been established as a tissue-specific database for Arabidopsis circular RNAs [138]. Systematic studies of this special class of non-coding RNA have just begun in plants and much still remains to be uncovered about circRNAs in plants.

3.2 CircRNAs databases: Provide an efficient way to research circRNAs

Some circRNAs databases and techniques for studying circRNAs have come to the fore recent years, which provide an efficient way to research circRNAs (Table 4). And some research tools are developed, such as CircView: a tool to visualize and explore circRNAs [139], CircPro: a tool for the identification of circRNAs with protein-coding potential [140] and ISEScan: a tool for identification of ISES to discover circRNAs with translation function [141]. When we research circRNA as a ceRNA, we also need to use other databases like miRNA databases and gene analysis technology to find its downstream gene possible regulatory mechanisms.

4. Conclusion and outlook

CircRNAs, as a new discovered RNA family of ceRNAs, it is easy to detect them in human blood [64], saliva [154], tissue [108], even seminal plasma [155] and gastric juice [100] makes it has the potential to become a novel and convenient target molecule for disease diagnosis and treatment. Thanks to the development of high-throughput sequencing technologies and bioinformatics, they have become a popular research subject and gain more attention currently. Recently, a plethora of studies reported the expression of a variety of circRNAs in different species ranging from humans and animals to botanics. CircRNAs regulate gene expression at the transcriptional or post-transcriptional levels by acting as sponges for multiple miRNAs. The circRNA/miRNA/mRNA axis is proven to be strongly associated with the occurrence and development of various diseases. According to these characteristics, circRNAs could be served as biological markers of human diseases and brought the gospel for the animal and plant-related diseases as well.

However, at the same time, some questions have come into being. Some circRNAs have shown their complex specificity just like what we have pointed that same circRNA could be expressed differently in health and in different diseases and the levels of expression can also vary in the tissues within same organism. So, how do we use them to diagnosis a particular disease? In addition, some of circRNAs are detedted only in the tissue, it is inconvenient to detect them in tissues in the process of diagnosis of some diseases. And detecting circRNAs is much more expensive than the existing methods and the reliability of using circRNAs for diagnosis still needs to be proven. All of these questions or disadvantages will limit the widespread use of circRNAs as biomarkers. Numerous problems about circular RNA are unknown. The molecular mechanism underlying the involvement of the special interactions among this axis in the progression of human diseases remains to be discovered. It is yet unclear whether there is any other molecular mechanism of synthesis method of circRNAs.

Footnotes

Conflict of interest

The authors declare that they have no competing interest.

Abbreviations

circRNAs	Circular RNAs
miRNAs/miR	microRNAs
lncRNAs	long, non-coding, RNAs
ceRNA	competing endogenous RNA
MREs	microRNA response elements
CDR1	cerebellum degeneration-related protein 1 antisense
RBPs	RNA-binding proteins
RPCs	RNA-protein complexes
IRES	inserted an internal ribosome entry sites
UBE2A	Ubiquitin-conjugating enzyme E2 A
EGFR	epidermal growth factor receptor
SNCA	$\alpha$ -synuclein
IRS2	insulin receptor substrate-2
MBL	muscleblind
Myrip	myosin VIIA and Rab interacting protein
PAX6	Paired box protein
VEGF-C	Vascular endothelial growth factor C
FZD4	frizzled-4
MMP13	Matrix metallopeptidase 13
NAMPT	nicotinamide phosphoribosyl transferase
IGF1R	insulin-like growth factor I receptor
PPAR $\alpha$	peroxisome proliferator-activated receptors $\alpha$
Col1a2	collagen type I alpha 2 chain
CTGF	connective tissue growth factor
ARC	Apoptosis repressor with CARD domain
PARP	poly ADP-ribose polymerase
TGF- $\beta$ 1	transforming growth factor- $\beta$
COX-2	Cyclooxygenase-2
MMP-9	matrix metalloprotein-9
PPAR $\gamma$	peroxisome proliferator-activated receptor $\gamma$
FGF2	Fibroblast Growth Factor 2
HIF-1 $\alpha$	hypoxia-inducible factor-1 $\alpha$
MTP-18	Mitochondrial Protein 18
ncRNA	non-coding RNA
GO	Gene Oncology
KEGG	Kyoto Encyclopedia of Genes and Genomes
CDC42	Cell division control protein 42
CDK6	cyclin dependent kinase 6
VEGFA	vascular endothelial growth factor A

HSPE	heparanase
CCNE1	cyclin E1
PIK3CD	phosphatidylinositol 3-kinase catalytic deltapolypeptide
p70S6k	p70 ribosomal protein S6 kinase
PD-1	programmed cell death-1
TERT	telomerase reverse transcriptase
LATS1	Large Tumor Suppressor 1
ERF2	Ethylene-responsive transcription factor 2
Bcl-2	B-cell lymphoma 2
IL6R	Interleukin 6 Receptor
GFRA1	GDNF Family Receptor Alpha 1
E2F3	E2F transcription factor 3
GLS	Glutaminase
CCND2	cyclin D2
PTEN	Phosphatase And Tensin Homolog
CCNG1	cyclin G1
ZFPM2	Zinc Finger Protein, FOG Family Member 2
E2H2	Enhancer of zeste homolog 2
HNF1 $\beta$	hepatocyte nuclear factor 1 homeobox
Derlin-1	degradation in endoplasmic reticulum protein 1
PD	Parkinson’s disease
IRI	ischemia-reperfusion injury
AD	Alzheimer’s disease
CVD	Cardiovascular diseases
SRY	sex-determining region Y
T2DM	Type 2 Diabetes
PBMCs	peripheral blood mononuclear cells
MDD	depressive disorder
IDD	intervertebral disc degeneration
HSCC	hypopharyngeal squamous cell carcinoma
LSCC	laryngeal squamous cell cancer tissues
PDAC	Pancreatic ductal adenocarcinoma
HCC	hepatocellular carcinoma
PTC	papillary thyroid carcinoma
GBM	glioblastoma multiforme
ccRCC	clear cell renal cell carcinoma
TNBC	Triple negative breast cancer
CSCC	Cutaneous squamous cell carcinoma
ESCC	esophageal squamous cell cancer
NSCLC	Non-small cell lung cancer
TNBC	Triple negative breast cancer
LSCC	Laryngeal squamous cell cancer
AML	Acute myeloid leukemia
OS	Osteosarcoma
ALV-J	Avian leukosis virus subgroup

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Circular RNAs as novel rising stars with huge potentials in development and disease

Abstract

Keywords

1. Introduction

1.2 CircRNAs function as miRNAs sponges

1.3 CircRNAs interact with RNA-binding proteins

1.4 CircRNAs are involved in the regulation of gene transcription

1.5 Few circRNAs could be translated

Table 1 Summary circRNAs acting as miRNAs sponges in non-cancer diseases

2.1 CircRNAs and non-cancer diseases: Novel rising stars

Table 2 Summary of the expression of circRNAs acting as miRNA sponge in carcinomas

Table 4 circRNAs databases

3.1 Expression of circRNAs in plants

3.2 CircRNAs databases: Provide an efficient way to research circRNAs

4. Conclusion and outlook

Footnotes

Conflict of interest

Abbreviations

References

Table 1
Summary circRNAs acting as miRNAs sponges in non-cancer diseases

Table 2
Summary of the expression of circRNAs acting as miRNA sponge in carcinomas

Table 4
circRNAs databases