Experimental Cell Research 368 (2018) 147–158

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Experimental Cell Research

journal homepage: www.elsevier.com/locate/yexcr

The mechanism and function of circular RNAs in human diseases T

a,1 a,1 a b a a,⁎
Kexin Lei , Hetian Bai , Zihao Wei , Changqing Xie , Jiongke Wang , Jing Li ,
Qianming Chena
a
State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, China
b
Xiangya Stomatological Hospital, Central South University, Changsha, China

A R T I C LE I N FO A B S T R A C T

Keywords: Circular RNAs (circRNAs) are a recently discovered form of RNA. Initially, circRNAs were believed to result from
CircRNA errors during the process of gene transcription. However, after further investigation, scientists suggested that
Biology function circRNAs are of great biological significance. CircRNAs show stability, conservation, abundance, and tissue and
Central neural system diseases stage specificity. They can also function as miRNA sponges, regulate gene expression, and interact with proteins
Cardiovascular diseases
to affect cell behavior. Emerging evidence has also demonstrated that circRNAs participate or show abnormal
Cancer
expression in diseases, including central nervous system diseases, cardiovascular diseases and cancers, indicating
their marked potential in the prediction and prognosis of diseases and clinical treatment.

1. Introduction
Circular RNAs (circRNAs) are an emerging member of long non-
coding RNAs (lncRNAs) [1]. Unlike linear RNAs, which are equipped
with 5′ caps and 3′ tails, circRNAs feature a covalently closed loop
structure. Therefore, they are not susceptible to RNases, and this con-
fers higher stability in comparison with linear RNAs [2]. CircRNAs can
originate from exons (exonic circRNAs) [3], introns (intronic circRNAs)
[4], or both (exon-intron circRNAs) [5], as well as tRNAs (tricRNAs)
[6]. To date, scientists have found more than 100,000 types of circRNAs
and have revealed high sequence conservation among circRNAs derived
from different species [3]. They are of great significance in processes
such as regulating RNA transcription [7], sponging miRNAs [8,9],
sponging proteins [10], interacting with proteins [11], and translating
proteins [12–15]. CircRNAs are involved in the pathogenesis of various
diseases, and their diverse functions, their newly discovered abun-
dance, prevalence, stability make them a hotspot in biological fields
[16]. CircRNAs are also potentially valuable as biomarkers and ther-
apeutic targets in diseases diagnosis and treatment. [17]. In this review,
we concisely describe the mechanisms of formation and biological
functions of circRNAs, and we highlight the relationship between cir-
cRNAs and diseases, especially for carcinomas.
2. Biogenesis of CircRNAs
In eukaryotes, canonical splicing is organized by spliceosomal
machinery which removes introns and joins exons into a linear RNA
transcript [18]. When circRNA was found more than two decades ago
by Nigro et al.[19], it was thought to be derived from aberrant RNA
splicing [20]. Unlike its lariat counterpart, circRNA lacks a 5′ cap or 3′
poly-A tail and is circularized by covalent bonds. CircRNA can be
generated from exonic, intronic, and intergenic regions, as well as 5′ or
3′ untranslated fragments [21,22]. There are three main categories of
circRNAs: exonic circRNAs (ecircRNAs), circular intronic RNAs
(ciRNAs), and exonic-intronic circRNAs (EIciRNAs) (Fig. 1).
Most ecircRNAs originate from exons. There are two steps involved:
1) the upstream intron of one or more exon pairs joins with the
downstream intron, and 2) the 2′ hydroxyl of the upstream intron reacts
with the 5′ phosphate of the downstream intron, followed by the 3′
hydroxyl of the 3′ exon reacting with the 5′ phosphate of the 5′ exon,
leading ultimately to the formation of the circRNA [23]. The ALU se-
quences in the introns can also interact with each other to promote
back-splicing [24]. Some RNA-binding proteins serve as regulatory
factors in this process. For example, Muscleblind (MBL) links proximal
flanking introns, promoting the production of circRNAs [10], and the
RNA-editing enzyme adenosine to inosine acting on RNA enzyme 1
(ADAR1) inhibits circRNA formation [7]. Moreover, lariat-driven cir-
cularization is another mechanism to produce circRNAs. The upstream
splice acceptor and downstream donor are in close proximity due to the
lariat, and the exons in the spliced lariat are then joined by a 5′–3′
phosphodiester bond [25]. In the process of ecircRNA formation, after
the circular structure is formed, the introns are removed or retained to

⁎
Corresponding author.
E-mail address: lijing1984@scu.edu.cn (J. Li).
1
Contributed equally.

https://doi.org/10.1016/j.yexcr.2018.05.002
Received 8 December 2017; Received in revised form 30 April 2018; Accepted 2 May 2018
Available online 03 May 2018
0014-4827/ © 2018 Elsevier Inc. All rights reserved.
K. Lei et al.
portant for the formation of ciRNA. The terminal 2′ hydroxyl group of the intron approaches the 5′ splice site, creating a circular RNA by forming a 2′–5′ phos-
phodiester bond. E. The pre-tRNA was spliced into two parts by tRNA splicing enzymes: the termini of one part are bound by a 3′–5′ phosphodiester bond, forming a
circular RNA, and the other part generates tRNAs.
generate EIciRNAs [3]. Moreover, ciRNAs can be derived from an in-
tron lariat; a unique 2′–5′ linkage between two termini is produced, and
after the tail is trimmed, a ciRNA is formed. A GU-rich sequence near
the 5′ splice site and a C-rich sequence near the branch point are very
important for the formation of a ciRNA [22]. In addition, ciRNAs pre-
dominantly exist in the nucleus, and their functions may be different
from cytoplasmic RNAs. Furthermore, a new type of ciRNA, called
TricRNA, is derived from pre-tRNA splicing [26]. This type of ciRNA is
produced when the introns are removed from pre-tRNA by tRNA spli-
cing enzymes, and a 3′–5′ phosphodiester bond is formed between the
termini of the introns to generate the TricRNA [27].
3. Functions of CircRNAs
Various functions of circRNAs have been discovered, and here, we
categorize them into five main types: 1) regulation of linear RNA
transcription, 2) miRNA sponges, 3) protein sponges, 4) interactions
with different proteins to influence their biological functions, and 5)
protein translation (Fig. 2).
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Experimental Cell Research 368 (2018) 147–158
Fig. 1. Biosynthesis of circRNA. A. The
downstream introns and upstream introns of
one or more than one exon are paired based on
an inverse repeating sequence; then, the 2′
hydroxyl of the upstream intron reacts with the
5′ phosphate of the downstream intron; the 3′
hydroxyl of the downstream exon reacts with
the 5′ phosphate of the upstream exon, after
which an ecircRNA or EIciRNA, when the in-
trons are not removed, is produced. B. When a
preRNA is spliced, the 3′ hydroxyl of the up-
stream exon interacts with the 5′ phosphate of
the downstream exon and forms a covalent
bond, producing a lariat that contains exons
and introns. The 2′ hydroxyl of the 5′ intron
reacts with the 5′ phosphate of the 3′ -intron,
followed by an interaction between the 3′ hy-
droxyl of the 3′ exon and the 5′ phosphate of
the 5′ exon, through which an ecircRNA is
formed. C. Some RNA-binding proteins (RBPs)
can promote the interaction of the downstream
intron and upstream intron, causing the circu-
larization of a preRNA. D. Biosynthesis of
ciRNA. The prior release of the 3′ exon is im-
3.1. Regulation of linear RNA transcription
CircRNAs influence the splicing processes and are key regulators in
alternative splicing and transcription (Fig. 2A). They not only increase
the transcription of linear RNAs but also suppress their transcription.
CircRNAs form from exons are the major species, which make synthetic
production process compete with canonical splicing. On the one hand,
pre-mRNAs are modified though canonical splicing to form linear
RNAs, and exons are indispensable for this process; thus, when the
formation of circRNAs and linear RNAs requires a common exon, the
two procedures compete with one another. Furthermore, the two pro-
cesses are likely to share the same sites [28]. EcircRNAs may act as an
“mRNA trap” by sequestering the translation start site, inhibiting the
translation of truncated RNAs [29].
As for circRNAs formed from introns, such as ciRNAs and EIciRNAs,
there are advanced studies revealing that these circRNAs modulate the
expression of parental genes. It has been demonstrated that some
ciRNAs or EIciRNAs, such as c-sirt7, are derived from lariats and can
interact with the polymerase II complex. As a result, the expression
Fig. 2. Functions of circRNA. A. CircRNAs
are formed from pre-mRNAs and have en-
dogenous effects on linear RNA transcription.
This effect can be promoting or suppressing the
transcription of linear RNAs. If the circRNAs
and linear RNAs share a common exon, the two
formation processes compete, while ciRNAs
and EIciRNAs enhance linear RNA transcrip-
tion. B. CircRNAs with complementary se-
quences can bind to their target miRNAs to
inhibit the impact of miRNAs. The miRNA
sponge function can also serve as a method of
storing and carrying miRNAs. C. CircRNAs can
act as sponges for RBPs (RNA-binding proteins)
to regulate the levels of these proteins, and
they can also be used to transport proteins. D.
CircRNAs can bind to various proteins and start
a series of signal transduction pathways to
regulate biological functions of proteins. E.
CircRNAs can translate peptides or proteins.
K. Lei et al.
levels of the corresponding genes ankyrin repeat domain 52
(ANKRD52) and sirtuin 7 (SIRT7) decline [30]. As mentioned, during
their formation, these circRNAs regulate the expression of their par-
ental genes, and this is one of the preconditions for circRNAs to play a
role in other functions.
3.2. miRNA sponges
In recent years, an increasing number of circRNAs have been vali-
dated as miRNA sponges [31,32] (Fig. 2B). MiRNAs are known to act as
regulatory non-coding RNAs that play a role in suppressing downstream
mRNAs to repress protein synthesis. Previously, it was generally ac-
knowledged that competitive endogenous RNA (ceRNA) includes a
miRNA response element (MRE). Consequently, ceRNAs bind to miRNA
and reduce the inhibition of gene expression. Recently, researchers
have demonstrated that circRNAs with complementary sequences can
bind to their target miRNAs, thereby inhibiting the function of those
miRNAs [9]. However, whether or not the sponge phenomenon is a
universal function of circRNAs is still under discussion.
CiRS-7, also named CDR1as, has been clearly demonstrated to
function as a typical example of a miRNA sponge [29,33–35]. CiRS-7,
with more than 70 conventional miR-7 binding sites, is formed from the
antisense transcript of the CDR1as gene [33]. Additionally, ciRS-7
cannot be degraded by the RNA-induced silencing complex (RISC),
which is mediated by miR-7, but can complement miR-671 for de-
gradation [36]. Furthermore, miR-7 is one of the key players in nu-
merous signaling pathways, and components of the ciRS-7–miR-7 axis
are widely expressed in various carcinomas, such as astrocytoma and
lung cancer [37]. Notably, the murine sex-determining region Y (SRY)
also forms a circRNA that can harbor 16 seed matches to bind to miR-
138 [35,38,39].
3.3. Protein sponges
CircRNAs can also act as sponges for RNA-binding proteins (RBPs)
to regulate protein levels (Fig. 2C). For example, circMBL, which was
discovered in flies and humans, can bind to MBL protein at multiple
binding sites [9]. In fact, RBPs are involved in almost all cellular pro-
cesses, including proliferation, apoptosis, and differentiation.
3.4. Interaction with proteins
In recent years, more and more investigations have suggested that
some circRNAs can also interact with proteins to influence cellular
behavior (Fig. 2D and Fig. 3). For example, circFOXO3, one of the
circRNAs that is currently receiving the most attention, was demon-
strated to serve as an adaptor bridging p21 and cyclin-dependent kinase
2 (CDK2) [40]. CircFOXO3 promotes the release of CDK2 from p21,
which can then phosphorylate cyclin A and cyclin E, to facilitate the cell
cycle. Moreover, circFOXO3 assists in bringing p53 and murine double
minute2（MDM2）together, accelerating the degradation of p53 [41].
ID-1, E2F1, FAK, and HIF1α have been demonstrated to interact with
circFOXO3 as well. CiRS-7, circMBL, circ-Amotl1, and circ-ANRIL are
also able to bind to specific proteins.
3.5. Protein translation
Although circRNA lacks the 5′ 7-methylguanosine cap structure and
poly(A) tail, which are two essential features for translation of linear
RNA, scientists recently found that circRNA can also be translated into
protein or peptides (Fig. 2E). In 1995, the initial study found that the
encephalomyocarditis virus internal ribosome entry site (IRES) plays an
important role in translation of an artificial circRNA [12]. Moreover,
recently, Yang et al. first demonstrated that N6-methyladenosine
(m6A), the most common modification of RNA, promotes the transla-
tion of circRNA in human cells, suggesting a role for circRNA-derived
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Experimental Cell Research 368 (2018) 147–158
proteins in response to external stress. The mechanism is initiated by
eIF4G2 and the m6A reader YTHDF3, and it is promoted by the me-
thyltransferase METTL3/14 and inhibited by the demethylase FTO
[42]. Interestingly, scientists found these circRNAs are mostly trans-
lated by membrane-associated ribosomes and have evolutionarily con-
served termination codons [43,44]. Although some studies have been
carried out, the details of translation of circRNA remain unknown and
require additional effort from scientists.
4. The role of CircRNAs in human diseases
As more functions of circRNAs are revealed, the underlying re-
lationships between circRNAs and various diseases have been rapidly
elucidated. Studies focusing on circRNAs and diseases, such as central
nervous system diseases, cardiovascular diseases, and especially carci-
noma, are numerous and well developed. The great specificity and
conservation in various tissues add a further dimension to the discovery
of these disease biomarkers. In this section, we shall list new experi-
mental progress that bears upon clinical diseases.
4.1. CircRNAs and central nervous system diseases
Several studies have indicated that circRNAs are more abundant in
the brain than in other tissues, and this abundance may offer some clues
to circRNA-related nervous system disorders [45–49]. As the central
nervous system ages, age-related circRNAs accumulate in the brain and
have been identified as promising indicators of aging. Furthermore,
some circRNAs are closely related to central nervous system toxicity
caused by foreign objects. Here, we mainly focus on diseases of aging,
such as AD and Parkinson's disease, and neural injuries (Fig. 4).
Moreover, the circRNAs involved in central nervous system diseases
and their targets and functions are presented in Table 1.
4.1.1. CircRNAs and neurodegenerative diseases
CircRNAs are frequently expressed from neural genes and accumu-
late in brain tissue during aging [50]. Anatomical studies clearly verify
that brain tissues show great enrichment in circRNAs, and they are
present in synaptic compartments more than in axonal or dendritic
shafts, which may indicate that they are positioned to participate in
physiological processes within the synapse [45,46]. Due to the link
between circRNAs and the nervous system, researchers have found that
circRNAs play roles in neural disorders, such as Alzheimer's disease
(AD), Parkinson's disease, and schizophrenia [51,52] (Fig. 4A). Re-
searchers have discovered that dysregulation of the interaction between
ciRS-7 and miR-7 is crucial for neural disorders [53]. Cells in brains
with AD intrinsically lack ciRS-7 and its sponge effects. Consequently,
the level of miR-7 increases, and the expression of miR-7-sensitive
mRNA is down-regulated. For example, in the progressive pathological
process of AD, ubiquitin-conjugating enzyme E2A（UBE2A）, a vital
autophagic protein that can remove amyloid peptides, is severely de-
pleted [52]. This shortage of UBE2A thus leads to the accumulation of
amyloid peptides and the aggregation of age pigments [54]. In sum-
mary, the imbalance of ciRS-7-miR-7-UBE2A signaling circuit con-
tributes to sporadic AD, and the potential of ciRS-7 to become a bio-
marker for neurodegenerative disorder requires further study [53].
4.1.2. CircRNAs and neural injuries
It is widely known that lead is a metal that can induce neurotoxicity.
Recently, mouse models of lead poisoning demonstrated the up-reg-
ulation of the apoptosis-related circRNA (circRar1) in the hippocampus
and cerebral cortex. The mechanism is also related to microRNA sponge
activity, specifically, circRar1 targets miR-671, which inhibits apoptosis
(Fig. 4B). The suppression of miR-671 results in up-regulation of the
apoptosis-associated proteins caspase-8 and p38 to promote neuronal
apoptosis [55]. Furthermore, cerebral ischemia-reperfusion injury (IRI)
is a common injury phenomenon in the central nervous system that
K. Lei et al. Experimental Cell Research 368 (2018) 147–158

Fig. 3. CircRNAs can interact with various

proteins. CircRNAs can bind with proteins to
influence physiological or pathological pro-
cesses. A. ciRS-7 can interact with AGO2 to
competitively bind to miR-7, and this is a
common process in many diseases, such as
cancer. B. circMBL promotes its own formation
by binding with MBL. C. circ-FOXO3 can in-
teract with ID-1, E2F1, FAK and HIF1α,
leading to the retention of these factors in the
cytoplasm and contributing to the aging pro-
cess. It can also interact with p21 and CDK2,
which promote the inhibition of CDK2 by p21,
thereby regulating the cell cycle. It can interact
with MDM2 and p53, increasing the MDM2-
induced ubiquitin-mediated degradation of
p53. Moreover, circ-FOXO3 binds weakly to
FOXO3, inhibiting the binding of FOXO3 and
MDM2 and thereby promoting the accumula-
tion of FOXO3. D. circ-Amotl1 guides c-Myc to
enter the nucleus, leading to tumorigenesis;
circ-Amotl1 and circ-Stat3 have common
binding sites in the Dnmt3a promoter region,
where they can interact with each other and
play a role in wound healing. E. circANRIL
binds to lysine-rich domains in the C terminus
of PES1, competitively inhibiting the interac-
tion of PES1 and ribosomal components to regulate ribosome formation.

Fig. 4. CircRNAs play a crucial role via their

sponge function in diseases of the central
nervous system. A. In central nervous system
diseases, ciRS-7 can bind to miR-7, which gives
rise to UBE2A, a vital protein for clearing
amyloid peptides in the brain. This protective
pathway has been identified in Alzheimer's
disease and other neurodegenerative disorders.
B. Lead is a neurotoxic metal that leads to
neuronal apoptosis. In a mouse model of lead
poisoning, circRar1 is up-regulated and binds
to its target miR-671. As a result, caspase-8 and
p38 levels increase, inducing apoptosis. C. In
oxygen glucose deprivation/reoxygenation
(OGD/R) models, mmu-circRNA-015947 is up-
regulated and is verified to act as a sponge for
five miRNAs (mmu-miR-188-3p, mmu- miR-
329-5p, mmu-miR-3057-3p, mmu-miR-5098
and mmu-miR-683) to mediate 99 genes.

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K. Lei et al.
Table 1
CircRNAs involved in central neural system diseases and their targets, functions.
CircRNA Target
circRar1 miR-671
circRNA_008008, circRNA_013779 et. Not clear
ciRS-7 miR-7，UBE2
mmu-circRNA-015947 mmu-miR-188–3p, mmu-
miR-329–5p, mmu-miR-
3057–3p, mmu-miR-5098
and mmu-miR-683)
circ_008018, circ_015350, and circ_016128 Not clear
upregulated;circ_011137, circ_001729, and
circ_006696 downregulated
CiRS-7(Cdr1as) miR-7, miR-671
hsa_circRNA_103636 Not clear
often occurs after cerebral ischemic diseases such as acute ischemic
stroke [56]. It is extremely important to treat IRI in a timely manner to
avoid the risk of ischemic failure, which can be fatal, in other organs of
the body [57]. A recent study indicated that mmu-circRNA-015947 is
up-regulated in oxygen glucose deprivation/reoxygenation (OGD/R)
models and that 5′-downstream miRNAs (mmu-miR-188-3p, mmu-miR-
329-5p, mmu-miR-3057-3p, mmu-miR-5098 and mmu-miR-683) can be
targeted though a circRNA-miRNA-gene pathway (Fig. 4C). Through
gene prediction, there are 99 genes that have been verified to partici-
pate in the aforementioned pathways, the concrete mechanism remains
unclear [58].
Hundreds of circRNAs are highly abundant in mammalian brain. In
neurons, circRNAs are expressed in the soma and in neurites and have
the overall highest concentration in synaptosomes [59]. circRNAs play
their roles not only in normal brain function [60] but also in central
nervous system diseases. In particular, neurodegenerative disease is a
widespread health problem for which there are no effective preventive
measures. These findings suggest that monitoring specific circRNAs
may be useful for diagnosing aging-related diseases of the nervous
system or neural injuries.
4.2. CircRNAs and cardiovascular disease
Cardiovascular disease (CVD) poses an increasing threat to human
health. According to a report from the World Health Organization
(WHO), nearly 17.5 million people die of CVD each year [61]. The need
to identify and develop effective approaches to prevention and treat-
ment of CVD is undeniable. As acknowledged, circRNAs are highly
specific and are exclusively expressed in different tissues, including
vascular and heart tissue. In human peripheral whole blood, scientists
have derived 4550 and 4105 unique circRNAs from two volunteers, and
the expression levels of these circRNAs are much higher in blood than
in other tissues such as liver and cerebellum [62]. Researchers have
uncovered 15,318 and 3017 cardiac circRNAs from 12 human hearts
and 25 mouse hearts [63]. The substantial number of highly expressed,
stable circRNAs in human vascular tissue and the heart shows great
promise as a CVD biomarker [64]. In the next section, we elaborate
several classical or newly discovered pathways that indicate the role of
circRNAs in cardiac hypertrophy, cardiac fibrosis, myocardial infarc-
tion, and atherosclerosis (Fig. 5). The circRNAs involved in central
cardiovascular diseases and their targets and functions are presented in
Table 2.
Experimental Cell Research 368 (2018) 147–158
Function Quotation
Promote lead-induced neuronal A novel regulatory network among LncRpa, CircRar1,
apoptosis MiR-671 and apoptotic genes promotes lead-induced
neuronal cell apoptosis
Induce neuropathic pain Chronic constriction injury of sciatic nerve changes
circular RNA expression in rat spinal dorsal horn
Deficits in ciR-7 increase ambient Circular RNA (circRNA) in Alzheimer's disease (AD);
miRNA-7 level in Alzheimer's Deficiency in the Ubiquitin Conjugating Enzyme UBE2A
disease and Parkinson's disease in Alzheimer's Disease (AD) is Linked to Deficits in a
Natural Circular miRNA-7 Sponge (circRNA; ciRS-7)
Induce cerebral ischemia- Circular RNA expression alterations are involved in
reperfusion injury OGD/R-induced neuron injury
Alter after transient focal ischemia Circular RNA Expression Profiles Alter Significantly in
in mouse brain Mouse Brain After Transient Focal Ischemia
Lead to neuropsychiatric disorders Loss of a mammalian circular RNA locus causes miRNA
deregulation and affects brain function
Decreased in major depressive hsa_circRNA_103636: potential novel diagnostic and
disorder therapeutic biomarker in major depressive disorder.
4.2.1. CircRNAs and cardiac hypertrophy
Pathological cardiac hypertrophy is a prophase of heart failure. A
previous study claimed that miR-223 is a contributing factor in cardiac
hypertrophy and heart failure [65,66]. However, heart-related circRNA
(HRCR) has six target sites for miR-223, can serve as an endogenous
miR-223 sponge, and indirectly enhances the expression of the down-
stream target apoptosis repressor with caspase recruitment domain
(ARC), which has been proven to be a myocardial protective factor
[67,68] (Fig. 5A). Hence, HRCR attenuates the pathogenesis of cardiac
diseases [69]. New models incorporating HRCR, miR-223 and ARC
provide insight into heart-related disorders.
4.2.2. CircRNAs and cardiac fibrosis
Cardiac fibrosis is a common type of degeneration triggered by
hyperfunction of fibroblasts, which differentiate into myofibroblasts
[70]. Consequently, redundant extracellular matrix is secreted and ac-
cumulates in the myocardium. The pressure caused by the hard, fibrous
tissues leads to the extrusion of normal cardiac tissue and is likely to
induce heart remodeling [71].
Generally, diabetes patients are at a higher risk of suffering from
diabetic cardiac fibrosis [72]. Tang et al. investigated diabetic db/db
mice, and circRNAs-profiling arrays revealed that 76 circRNAs were
abnormally expressed, including 45 up-regulated and 31 down-regu-
lated circRNAs. Among them, circRNA-000203 was particularly highly
overexpressed. Further investigation showed that circRNA-000203 can
directly act as a sponge for miR-26b-5p, which inhibits the expression
of fibrosis-related genes, including Collagen Type I Alpha 2 Chain
(Col1a2) and Connective Tissue Growth Factor (CTGF), in cardiac fi-
broblasts. CircRNA-000203 abolishes the anti-fibrotic effect of miR-
26b-5p and enhances the expression of Col1a2, CTGF, Collagen Type III
Alpha 1 Chain (Col3a1), and α-SMA, thereby resulting in cardiac fi-
brosis [73].
Another parallel study analyzed the relationship between circRNAs
and cardiac fibrosis. Similarly, in the myocardium of diabetic mice,
Zhou et al. focused on circRNA-010567, which was visibly up-regulated
in tissue samples [74]. Analysis suggested that circRNA-010567 can
directly bind to and negatively regulate miR-141. TGF-β1, the down-
stream target that is inhibited by miR-141, mediates the formation of
fibrous proteins (Fig. 5B). In contrast, circRNA-010567 knockdown
alleviates the synthesis of fibrous proteins such as Col1, Col3 and α-
SMA.
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K. Lei et al. Experimental Cell Research 368 (2018) 147–158

Fig. 5. CircRNAs are involved in various

cardiovascular diseases. A. Heart-related
circRNA (HRCR) can serve as a miR-223
sponge to attenuate the inhibitory effect of
miR-223 on its downstream target ARC. Thus,
the heart-protective factor ARC will prevent
the pathogenesis of cardiac hypertrophy. B.
CircRNA-000203 and circRNA-010567 have
similar functions in cardiac fibrosis. CircRNA-
000203 binds to miR-26b-5p while circRNA-
010567 binds to miR-141, but both induce the
generation of a series of fibrous proteins, such
as Col1, Col3, α-SMA and CTGF, to accelerate
the process of cardiac fibrosis. C. The pro-
apoptotic genes PARP and SP1 are target genes
of miR-7 and can induce cardiomyocyte apop-
tosis and myocardial infarction.
Overexpression of ciRS-7 alleviates the pro-
tective effect of miR-7 and causes harm to
cardiomyocytes. D. CircRNA mediates the
process contributing to atherosclerosis. The
human chromosomal locus 9p21 is closely re-
lated to atherosclerosis and other cardiovas-
cular diseases. ANRIL (antisense noncoding
RNA in the INK4 locus) is an anti-sense non-
coding RNA encoded in the 9p21 region.
Linear ANRIL can also be converted to
circRNA. CircANRIL can interact with the 60S-
preribosomal assembly factor PES1 and inhibit
exonuclease-mediated processing and ribo-
somal formation in cardiomyocytes. As a re-
sult, cancer suppressor genes, such as p14, p15,
and p16, are silenced, and there is a higher risk
of suffering from atherosclerosis.

4.2.3. CircRNAs and myocardial infarction
Similar to other cardiovascular diseases, myocardial infarction (MI)
is a fatal disease worldwide [75]. Previously, MI could not be predicted
effectively due to a lack of available biomarkers [76]. To date, several
studies have made significant headway in addressing this issue. In the
pathogenesis of MI, cardiomyocyte necrosis is caused by ischemia and is
a crucial factor leading to cardiomyocyte apoptosis [77]. Recently, the
circRNA ciRS-7 has been described to act as a sponge for the cardiac
protective factor miR-7, thereby enhancing MI [76,78]. Moreover, the
target genes of miR-7 have been identified as the pro-apoptotic genes
poly ADP-ribose polymerase (PARP) and SP1, which contribute to
myocardial damage [79] (Fig. 5C). Geng et al. reported that over-
expression of ciRS-7 aggravated the degree of cardiac infarct, while
overexpression of miR-7 had the opposite result [80]. The ciRS-7-miR-

Table 2
CircRNAs involved in cardiovascular diseases and their targets, functions.
CircRNA Target Function Quotation

HRCR miR-223,ARC Attenuate the pathogenesis of A circular RNA protects the heart from pathological
cardiac hypertrophy hypertrophy and heart failure by targeting miR-223
circRNA-000203 miR-26b- Induce cardiac fibrosis CircRNA_000203 enhances the expression of brosis-associated
5p,Col1a2 and genes by derepressing targets of miR-26b-5p, Col1a2 and
CTGF CTGF, in cardiac broblasts
circRNA-010567 miR-141,TGF-β Induce cardiac fibrosis A novel identified circular RNA, circRNA_010567, promotes
myocardial fibrosis via suppressing miR-141 by targeting TGF-
β1
CiRS-7(Cdr1as) miR-7 Induce myocardial infraction Circular RNAs in Cardiovascular Disease: An Overview;
Myocardial Infarction- Associated Circular RNA Predicting Left
Ventricular;Dysfunction Regulatory non-coding RNAs in acute
myocardial infarction
CircANRIL The INK4/ARF Regulate atherosclerosis Circular non-coding RNA ANRIL modulates ribosomal RNA
locus maturation and atherosclerosis in humans
hsa_circRNA_101238 hsa-miR-320a Participate in the process of Circular RNA expression pro le and potential function of hsa_
thoracic aortic dissection circRNA_101238 in human thoracic aortic dissection
hsa_circ_0010729 miR-186,HIF-1a Regulate vascular endothelial Circular RNA hsa_circ_0010729 regulates vascular endothelial
cell proliferation and apoptosis cell proliferation and apoptosis by targeting the miR-186/HIF-
1a axis
hsa_circ_0089378, hsa_circ_0083357, hsa_circ_0082824, hsa-miR- 130a- Promote TRPM3 expression by Circular RNAs promote TRPM3 expression by inhibiting hsa-
hsa_circ_0068942, hsa_circ_0057576, hsa_ 3p,TRPM3 inhibiting hsa-miR- 130a-3p in miR- 130a-3p in coronary artery disease patients
circ_0054537, hsa_circ_0051172, hsa_circ_0032970, coronary artery disease
hsa_circ_0006323
circ-Foxo3 ID1, E2F1, FAK, Induce cardiac senescence Microarray analysis shows that some microRNAs downregulate
HIF1a large numbers of target mRNAs,

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7-PARP/SP1 axis may offer new biomarkers for the diagnosis of MI,
while additional diagnostic markers remain to be discovered.
4.2.4. CircRNAs and atherosclerosis
In addition to the CVDs mentioned previously, circRNAs also have
roles in atherosclerosis, these functions are mediated by an alternative
mechanism rather than by circRNA sponge activity. CircANRIL can bind
with the crucial 60S-preribosomal assembly factor PES1 and depress
exonuclease-mediated processing and ribosomal formation in cardio-
myocytes [81]. This process silences cancer suppressor genes such as
p14, p15, and p16, which are essential for cardiovascular protection.
Consequently, the blocking effect promotes apoptosis initiation, which
plays a key part in atherosclerosis (Fig. 5D).
All in all, circRNAs play an essential role in the occurrence and
development of cardiovascular diseases via their multiple functions,
manifesting their potential utility in the diagnosis and treatment of
cardiovascular diseases.
4.3. CircRNAs and malignant carcinoma
CircRNAs are widely known to play significant functions in the in-
itiation and progression of solid tumors and hematological malig-
nancies, specifically as miRNA sponges, protein sponges, protein scaf-
folding, or splicing and transcription factors. According to the
literature, circRNAs have been implicated in several (5/10) of the
hallmarks of cancer, such as evading growth suppressors, sustaining
proliferative signaling, and evading cell death and senescence, as well
as angiogenesis, activation of invasion and metastasis [82]. Further-
more, the novel expression of circRNA in tumor cells, tissue-specificity,
diversity, and high stability make circRNAs promising biomarkers for
cancer. Below, several studies investigated the role of circRNA in cancer
are discussed. The circRNAs involved in cancer, as well as their targets
and functions, are presented in Table 3.
4.3.1. CircRNAs and hepatocellular carcinoma
According to the global cancer epidemiology statistics estimates,
hepatocellular carcinoma (HCC) is the third leading cause of death
across the world. A total of 748,000 new cancer cases and 695,900
cancer deaths were estimated in 2008, and half of those events occurred
in China [83]. Recently, the relationship between circRNA and HCC has
gained an increasing amount of attention from scientists. Yan et al.
identified candidate circRNAs based on RNA sequencing and associated
these candidate circRNAs with protein-coding genes (PCGs) using the
Genomic Regions Enrichment of Annotations Tool (GREAT). They
found significant alterations in circRNA expression between normal and
tumor issues. The PCGs associated with these candidate circRNAs also
showed distinguishing expression patterns [84]. More recently, scien-
tists have demonstrated that the expression of hsa_circ_0005075 differs
significantly between HCC and normal tissues in 60 matched tissue
samples, indicating that hsa_circ_0005075 is a potential biomarker
[85]. In addition, a difference in expression of hsa_circ_0001649 was
identified, revealing that the expression of hsa_circ_0001649 also cor-
related with tumor size and occurrence of tumor embolus [86]. It has
also been demonstrated that circZFR, circFUT8, and circIPO11 can be
used to distinguish liver cancer samples [87].
The functions of circRNAs in multiple signaling pathways or
through other mechanisms have been identified in a growing body of
evidence. The function of acting as a sponge for certain miRNAs gen-
erally regulates cancer-related gene expression. A recent study in-
vestigated the circRNA MTO1, which could suppress HCC by promoting
p21 expression by serving as a sponge for miR-9. Low expression of
circular MTO1 could aid in prediction of poor patient prognosis [88].
Similarly, Huang et al. revealed the regulatory role of the cir-
cRNA100338/miR-141–3p pathway in hepatitis B-related HCC [89].
The circRNA-related genes CDR1as [86] and zinc finger with KRAB and
SCAN domains 1 (ZKSCAN1) [90] both play a vital part in different
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Experimental Cell Research 368 (2018) 147–158
signaling pathways and networks. These studies demonstrated that the
expression of circRNAs is regulated in different ways and exert their
regulatory functions by multiple routes in HCC, indicating that circRNA
may be a suitable biomarker with clinical utility for HCC.
4.3.2. CircRNAs and gastric cancer
Gastric cancer (GC) is one of the leading causes of death among
males [91]. Since 2015, Li et al. initially demonstrated that circRNA
could be used in the screening of gastric cancer [92]. In recent years,
scientists have discovered more categories of circRNAs that can be
utilized as biomarkers for GC, leveraging the predictive value of the
circRNAs hsa_circ_0000745 [93], hsa_circ_0000705 [94], hsa_-
circ_0000190 [95], and circPVT1 [96]. A recent investigation con-
firmed that expression levels of circRNAs could predict the early re-
currence of stage III GC after radical surgery. First, they identified 46
circRNAs with different expression levels between tumor and normal
tissues. Then, they identified four significantly differentially expressed
circRNAs (hsa_circ_101308, hsa_circ_104423, hsa_circ_104916, and
hsa_circ_100269) and constructed a four-circRNA-based classifier to
evaluate whether the patients are at high or low risk, and this tool
produced statistically significant results [97]. Another biomarker of GC,
circRNA_100269, is down-regulated in GC and correlated with the
targeted miRNA, miR-630. Overexpression of the plasmid cir-
cRNA_100269 was confirmed to inhibit cell proliferation [98]. Fur-
thermore, circRNA_LARP4 has been proven to inhibit the proliferation
and invasion of GC via sponge activity toward has_miR-424-5p and
regulating the expression level of large tumor suppressor kinase 1
(LATS1), which is the core component of the Hippo signaling pathway
and acts as a suppressor in GC, revealing that circLARP4 may be a novel
tumor suppressive factor and a potential biomarker of GC [99]. More-
over, circ_hsa_circ_0003159 [100] and hsa_circ_0001895 [101] have
been shown to decrease in gastric cells, and they likely also play in-
dispensable roles during gastric carcinogenesis and are potential bio-
markers. Taken together, these findings suggest that circRNA plays a
key role in GC and holds great potential in clinical application.
4.3.3. CircRNAs and breast cancer
Lu et al. constructed a genome-wide circRNA profile and selected
candidate circRNAs for validation. Among the 1155 circRNAs that de-
monstrated differential expression between breast cancer tissues and
normal tissues, 715 are up-regulated, while 440 are down-regulated in
breast cancer tissues [102]. Indeed, some circRNAs that have recently
been under investigation were determined to promote the progress and
metastasis of breast cancer through various pathways, such as circ-
ABCB10, which functions as a sponge for miR-1271 [103]; circRNA
hsa_circ_0001982, which promotes breast cancer cell carcinogenesis
through decreasing miR-143 levels [104]; and circDENND4C, which
advances proliferation of breast cancer cells in hypoxic environments
[105]. Reports suggests that normal-adjacent tissues in the estrogen
receptor positive (ER+) subtype have relatively higher numbers of
circRNAs than other tumor samples within The Cancer Genome Atlas
(TCGA). A similar result was obtained using normal breast-mammary
tissues from the Genotype-Tissue Expression (GTEx) project [106].
4.3.4. CircRNAs and colorectal cancer
In 2015, Bachmayr-Heyda et al. initially validated the global re-
duction in circular RNA abundance in colorectal cancer (CRC) cell lines
(circular RNA expression 27.8%) compared to normal tissues (circular
RNA expression 78.1%). Furthermore, the ratios of circRNA to linear
RNA isoforms in tumors were all lower than in normal colon samples,
among which the ratio in colorectal cell lines was the highest [107].
Then, circRNA_001569 was determined to play a role in the prolifera-
tion and invasion of colorectal cancer. It was identified as a sponge for
miR-145 and as up-regulating miR-145 functional targets, namely, E2F
Transcription Factor 5 (E2F5), BCL2 Associated Athanogene 4 (BAG4),
and Formin Like 2 (FMNL2), which led to an increase in cells in the G2/
K. Lei et al. Experimental Cell Research 368 (2018) 147–158

Table 3
CircRNAs involved in cancers and their targets, functions.
CircRNA Target Function Quotation

hsa_circ_002059 Not clear Down-regulated in gastric cancer tissues Using circular RNA as a novel type of biomarker in
the screening of gastric cancer
hsa_circ_0000190 Not clear Down-regulated in gastric cancer Using circular RNA hsa_circ_0000190 as a new
biomarker in the diagnosis of gastric cancer
circ-Foxo3 MDM2 and p53 Decrease the expression of p53 and promote growth of Induction of tumor apoptosis through a circular RNA
tumor xenografts in breast cancer enhancing Foxo3 activity
circular RNA circITCH wnt/β-catenin signaling Exhibit a repressing effect in esophageal squamous cell Circular RNA ITCH has inhibitory effect on ESCC by
pathway carcinoma suppressing the Wnt/beta-catenin pathway
circular RNA circITCH Not clear Down-regulated in hepatocellular carcinoma tissues and Polymorphisms and expression pattern of circular
may have an inhibitory effect on hepatocellular RNA circ-ITCH contributes to the carcinogenesis of
carcinoma hepatocellular carcinoma
circular RNA ITCH miR-7 and miR-214 Inhibit lung cancer progress by enhancing expression of Circular RNA-ITCH Suppresses Lung Cancer
ITCH Proliferation via Inhibiting the Wnt/beta-Catenin
Pathway
circular RNA Circ ITCH miR-7,miR-20a,and miR- Down-regulated in colorectal cancer and participate in cir-ITCH Plays an Inhibitory Role in Colorectal
214 coloretal cancer Cancer by Regulating the Wnt/β-Catenin Pathway
hsa_circ_003570 not clear Down-regulated in not only hepatocellular carcinoma Decreased expression of hsa_circ_0003570 in
tissues but hepatocellular carcinoma cell lines hepatocellular carcinoma and its clinical significance
circTTBK2 miR-217 Promote cell proliferation, migration, and invasion, TTBK2 circular RNA promotes glioma malignancy by
while inhibit apoptosis regulating miR-217/HNF1β/Derlin-1 pathway
CiRS-7(Cdr1as) microRNA-7(miR-7) Promote EGFR expression via inhibit the expression of Quantitative Proteomics Reveals the Regulatory
microRNA-7(miR-7) to increased the proliferation of Networks of Circular RNA CDR1as in Hepatocellular
hepatocellular carcinoma cells Carcinoma Cells
CiRS-7(Cdr1as) miR-671-5p Repress the migration of glioblastoma multiforme cells Dysregulated miR-671-5p / CDR1-AS / CDR1 /
VSNL1 axis is involved in glioblastoma multiforme
cZNF292 wnt/β-catenin signaling Suppress tube formation by inhibiting the glioma cell Silencing of cZNF292 circular RNA suppresses human
pathway proliferation and cell cycle progress glioma tube formation via the Wnt/beta-catenin
signaling pathway
circHIPK3 miR-124 etc. Promote cell growth in hepatocellular carcinoma Circular RNA profiling reveals an abundant
circHIPK3 that regulates cell growth by sponging
multiple miRNAs
circMYLK miR-29a Promote the growth, angiogenesis and metastasis of Circular RNA MYLK as a competing endogenous RNA
bladder carcinoma promotes bladder cancer progression through
modulating VEGFA/VEGFR2 signaling pathway
circMTO1 miR-9 Suppress hepatocellular carcinoma progression by Circular RNA circMTO1 acts as the sponge of
acting as the sponge of oncogenic miR-9 to promote p21 microRNA-9 to suppress hepatocellular carcinoma
expression progression
circRNA_10033 miR-141-3p A tumor metastasis suppressor in various types of cancer Comprehensive circular RNA profiling reveals the
cells regulatory role of the circRNA-100338/miR-141-3p
pathway in hepatitis B-related hepatocellular
carcinoma
circPVT1 miR-125 family Down-regulate the expression of E2F2 in gastric cancer Circular RNA profile identifies circPVT1 as a
to promote cell proliferation proliferative factor and prognostic marker in gastric
cancer
circ-ABCB10 miR-1271 Promote breast cancer proliferation and progression Circular RNA circ-ABCB10 promotes breast cancer
proliferation and progression through sponging miR-
1271
hsa_circ_0013958 miR-134 Promote the proliferation and invasion of lung hsa_circ_0013958: a circular RNA and potential novel
adenocarcinoma biomarker for lung adenocarcinoma
circRNA UBAP2 miR-143 Enhance the expressison and function of anti-apoptotic Increased circular RNA UBAP2 acts as a sponge of
Bcl-2 to promote osteosarcoma growth and inhibit miR-143 to promote osteosarcoma progression
apoptosis
circRNA_100290 miR-29 family Inhibit the expression level of CDK6 by sponging miR-29 circRNA_100290 plays a role in oral cancer by
family to promote proliferation of oral cancer cell lines functioning as a sponge of the miR-29 family
circASXL1 Not clear Decrease the overall survival in bladder cancer and Expression of circular RNA circASXL1 correlates with
associate with TNM classification TNM classification and predicts overall survival in
bladder cancer
circTCF25 MiR-103a-3p/miR-107 Decrease expression of CDK6 to promote cell Screening differential circular RNA expression
proliferation, migration and invasion. profiles reveals the regulatory role of circTCF25-miR-
103a-3p/miR-107-CDK6 pathway in bladder
carcinoma
hsa_circ_0001649 Not clear Down-regulate in hepatocellar carcinoma Hsa_circ_0001649: A circular RNA and potential
novel biomarker for hepatocellular carcinoma
hsa_circ_0047905, Not clear Up-regulate as candidate oncogenes and act as tumor Analysis of co-expression networks for circular RNAs
hsa_circ_0138960， promoters in the pathogenesis of gastric cancer. and mRNAs reveals that circular RNAs
hsa_circ_7690-15 hsa_circ_0047905, hsa_circ_0138960 and has-
circRNA7690-15 are candidate oncogenes in gastric
cancer
hsa_circ_0016347 miR-214 Promote osteosarcoma cells proliferation Circular RNA hsa-circ-0016347 promotes
proliferation, invasion and metastasis of
osteosarcoma cells
(continued on next page)

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K. Lei et al. Experimental Cell Research 368 (2018) 147–158

Table 3 (continued)

CircRNA Target Function Quotation

hsa_circ-0004277 hsa-miR-3Dc-1–3p, hsa- Down-regulated in acute myeloid leukemia and may Characterization of hsa_circ_0004277 as a New
miR-571, hsa-miR-138-5p, serve as a biomarker Biomarker for Acute Myeloid Leukemia via Circular
hsa-miR-328-3p, hsa-miR- RNA Profile and Bioinformatics Analysis
692b
hsa_circRNA_103809 and Not clear Down-regulated in colorectal cancer and involved in Identification of differentially expressed circular
hsa_circ_104700 development of colorectal cancer RNAs in human colorectal cancer
hsa_circ_0005075 Not clear Participate in cell adhesion during hepatocellular Comprehensive Circular RNA Profiling Reveals That
carcinoma development hsa_circ_0005075, a New Circular RNA Biomarker, Is
Involved in Hepatocellular Crcinoma Development
circZKSCAN1 Several cancer-related Inhibit growth, migration, and invasion of ZKSCAN1 gene and its related circular RNA
signaling pathways hepatocellular carcinoma (circZKSCAN1) both inhibit hepatocellular carcinoma
cell growth, migration, and invasion but through
different signaling pathways
hsa_circ_0004018 Not clear Down-regulated and associated with tumor location, Screening differential circular RNA expression
tumor stage,Borrmann type,pathologic diagonosis,and profiles reveals hsa_circ_0004018 is associated with
tissue CA19-9 expression in gastric cancer hepatocellular carcinoma
hsa_circ_0003159 Not clear Down-regulated and negatively associated with gender, Reduced expression of circRNA hsa_circ_0003159 in
distal metastasis, and tumor-node-metastasis stage in gastric cancer and its clinical significance
gastric cancer
hsa_circ_0001895 Not clear Down-regulated and correlated with cell Decreased expression of hsa_circ_0001895 in human
differentiation,Borrmann type,and tissue gastric cancer and its clinical significances
carcino_embryonic in gastric cancer
hsa_circ_0000745 Not clear Down-regulated and plays an important role in GC and Circular RNA hsa_circ_0000745 may serve as a
its expression level in plasma in combination with CEA diagnostic marker for gastric cancer
level
hsa_circ-0013958 miR-134 Up-regulate the oncogenic cyclin D1 by sponging miR- hsa_circ_0013958: a circular RNA and potential novel
134 to promote the development of non-small cell lung biomarker for lung adenocarcinoma
cancer
circRNA_100876 Not clear Up-regulated and correlated closely with lymph node Over-expression of CircRNA_100876 in non-small cell
metastasis and tumor stagin lung cancer and its prognostic value
hsa_circ_0000069 Not clear Promote cell proliferation,migration,and invasion in Comprehensive profile of differentially expressed
colorectal cancer circular RNAs reveals that hsa_circ_0000069 is
upregulated and promotes cell proliferation,
migration, and invasion in colorectal cancer
circSMARCA5 Not clear Up-regulated and promotes cell proliferation Androgen-responsive circular RNA circSMARCA5 is
up-regulated and promotes cell proliferation in
prostate cancer
circ-FBXW7 Encode a functional Up-regulated and inhibits proliferation and cell cycle Novel Role of FBXW7 Circular RNA in Repressing
protein acceleration in glioma Glioma Tumorigenesis
hsa_circ_0067934 Not clear Promote proliferation of cells in esophageal squamous Circular RNA has_circ_0067934 is upregulated in
carcinoma esophageal squamous cell carcinoma and promoted
proliferation

M phase and a decrease in apoptosis in miR-145 expressing cells [108].
Similarly, hsa_circ_0020397 was determined to modulate the CRC cell
viability, apoptosis and invasion by interacting with miR-138 and
preventing down-regulation of telomerase reverse transcriptase (TERT)
and programmed death ligand 1 (PD-L1) [109]. In recent years, addi-
tional circRNAs have been detected as being expressed in novel patterns
in CRC cells, including circular BANP [110], up-regulation of hsa_-
circ_0000069 [111], and down-regulation of hsa_circ_103809 and
hsa_circ_104700 [112], indicating increased potential of circRNAs as
biomarkers and warranting further investigation in the occurrence and
progress of CRC.
4.3.5. CircRNAs and lung cancer
As one of the cancers with the highest incidence worldwide, lung
cancer has become a leading cause of death among cancer-related
diseases [113]. Although progress has been made recently in diagnosis
and treatment, other unknown mechanisms for timely diagnosis of lung
cancer are still being explored. Radon can induce pulmonary toxicity
and is a known human lung carcinogen, and it has recently been shown
to produce differential expression of several circRNAs [114]. This
suggests that circRNAs is involved in pulmonary toxicity induced by
radon. Researchers discovered that there are imbalances of 356 cir-
cRNAs in tumor samples. Among them, hsa_circRNA_404833 and
hsa_circRNA_406483 are strikingly over-expressed in tumor tissues
compared with adjacent tissues, which indicates that they are likely to
be useful as biomarkers in early-stage lung adenocarcinoma in pre-
diagnosis [115]. Simultaneously, Hsa-circ-0013958 was identified as
up-regulated in all of the lung adenocarcinoma tissues, and its expres-
sion level was associated with the TNM stage and lymphatic metastasis
[116]. More specifically, clinical studies and cellular studies both
confirm that circular RNA-ITCH (cir-ITCH) plays an inhibitory role in
lung cancer. The dysregulation of cir-ITCH may enhance the expression
of its parental anti-oncogene ITCH by sponge activity toward miR-7 and
miR-214 to regulate the proliferation of cancer cells [117].
4.3.6. CircRNAs and bladder cancer
In bladder cancer, circTCF25 was found to down-regulate miR-
103a-3p and miR-107 and to up-regulate cyclin-dependent kinases 6
(CDK6), which has been proven to promote the G1/S transition in the
cell cycle [118,119]. This might suggest circTCF25 as a new biomarker
[120]. Another investigation has proven that tumors with high cir-
cASXL1 expression are associated with shorter overall survival, and
multivariate analysis also reveals that circASXL1 may predict the
overall survival for patients with bladder cancer [121].
4.3.7. CircRNAs and leukemia
Salzman et al. studied the non-canonical mode of RNA splicing, and
they serendipitously found that hundreds of genes produced circRNAs
in acute myeloid leukemia (ALL), and those circRNAs were also de-
tected in HeLa cells [122]. Scientists also proved that hsa_circ_0004277
abnormal expression could be inhibited by chemotherapy in acute
myeloid leukemia [123].

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4.3.8. CircRNAs and other cancers
In epithelial ovarian carcinoma, a significantly larger number of
circRNAs were abnormally expressed in tumor sites compared to
normal sites, exhibiting a more robust expression pattern across pa-
tients than was observed for mRNA forms. Recently, scientists proved
that circRNA100290 could facilitate oral cancer via the
circRNA100290/miR-29b/CDK6 pathway [124]. In addition, circRNAs
have also been shown to play important roles in other cancers, such as
acute myeloid prostate cancer [125] and cutaneous squamous cell
carcinoma [126]. Consequently, they may be suitable as biomarkers in
cancer and offer new candidates for cancer treatment and prognosis
[127].
Cancer-related circRNAs and their corresponding miRNAs form a
circRNA-miRNA-mRNA axis that regulates the expression of cancer-
related proteins. Furthermore, the novel expression of circRNA in tumor
cells, tissue-specificity, diversity, and high stability identify circRNAs as
useful biological markers of human cancer, thus improving the accu-
racy and specificity of diagnostic biomarkers [120] and therapeutic
targets [128,129].
4.4. CircRNAs as emerging biomarker for human diseases
Previous studies confirmed that circRNAs play their essential role
not only in human normal tissues and organs function but also in the
occurrence and development of related diseases via their multiple
functions. Recently, circRNAs are emerging as a novel biomarker be-
cause of their conservation, abundance, cell type-specific and tissue-
specific expression, and their roles in disease progression. For example,
recent study have provided evidence that ciRS-7 has the potential to
become a biomarker for neurodegenerative disorder [130], or become a
new diagnostic biomarker of MI [131,132]; HRCR attenuates the pa-
thogenesis of cardiac diseases, has the potential to become a ther-
apeutic target [67,68]. CircRNA-000203 and circRNA-010567 have the
potential to become new diagnostic biomarkers of cardiac fibrosis
[67,68].
Scientists have carried out more studies about the functions of
circRNA in cancer than in other diseases. Thus, circRNAs are widely
known to play significant roles in the initiation and progress of cancer,
and they have been implicated in several (5/10) of the hallmarks of
cancer [67,68], particularly by acting as miRNA sponges. CircRNAs
regulate the expression of cancer-related proteins in various types of
human cancer through circRNA-miRNA-mRNA axis, such as hepato-
cellular [84,90], gastric [92,101], breast [102,105], colorectal
[107,112], lung [114,117], bladder [118,121], and other cancers, re-
present their potential as diagnostic markers, prognostic indicators,
therapeutic targets and even drug prospects in cancer. In addition, gene
fusion frequently occurs in blood system tumors and solid tumors
[133]. Fusion genes not only encode fusion proteins contributing to
diseases progression, but also generate non-coding RNAs. For example,
the circRNA generated by the MLL/AF9 fusion gene (fcircM9) in leu-
kemia [134], and the EML4-ALK fusion gene produces circRNA in
NSCLC [135]. Those circRNA generated by fusion gene may been used
as the molecular biology-specific markers for diagnosing different mo-
lecular types of tumor, and those fusion circRNA would provide new
insight into molecular targeting human disease treatment.
Furthermore, cells can secrete circRNAs via exosomes into the
blood, circular-to-linear RNA expression is generally higher in the blood
than in solid tissues, and circRNAs are expressed widely in blood,
saliva, and exosomes [136]. Given these characteristics, circRNAs could
be used as painless and minimally invasive biomarkers of human dis-
eases and thus improve the accuracy and specificity of diagnosis and
therapies. Fusion genes in disease may produce fusion circRNA.
Therefore, detection of circRNAs in patient could focus on more easily
acquired and non-invasive clinical samples, such as blood, urine, and
saliva, in the future research for developing circRNAs as clinical diag-
nostic biomarkers.
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Experimental Cell Research 368 (2018) 147–158
5. Conclusion and perspective
Overall, we provide a general map of circular RNA biology and
related diseases. The mechanisms of circRNA formation are diverse, and
they give rise to different types of circRNAs, which have different
functions such as regulating linear RNA transcription, absorbing
miRNAs and proteins, interacting with proteins and translating pro-
teins. These complex functions enable circRNAs to participate in the
occurrence and development of many diseases through a variety of
signaling pathways, especially for cancers. Actually, the majority of
circRNAs regulate diseases by acting as sponges, forming a circRNA-
miRNA-mRNA axis that regulates the expression of disease-related
proteins. As deep sequencing techniques and data analysis methods
evolve, we can further characterize different circRNAs in specific tissues
and the roles that they play in disease processes.
Nevertheless, circRNA nomenclature has not yet been standardized,
and the biogenesis and pathological pathways of circRNAs are not fully
understood. In addition, although the miRNA sponge function is cur-
rently the most studied function in disease, other mechanisms of action,
such as the regulation of gene or protein activities or protein transla-
tion, require further exploration. In the near future, the diagnosis and
treatment of diseases will gradually focus on genetic aspects with the
advent of precision medicine, and circRNAs, as a special type of non-
coding RNA, may play an important role in this process because of their
inherent characteristics.
Acknowledgements
This work was supported by National Natural Science Foundation of
China (Nos. 81672675 and 81621062), the 111 Project of MOE China
(Grant No. B14038), National Training Programs of Innovation and
Entrepreneurship for Undergraduates of China (number
201710612114), Creative innovation experiment project of college
students.
Conflicts of interest
The authors declare no potential conflicts of interest.
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