Circular RNAs as Novel Biomarkers
for Cardiovascular Diseases
Qiulian Zhou, Zhongrong Zhang, Yihua Bei,
Guoping Li, and Tianhui Wang
Abstract
Cardiovascular diseases are among the most
serious diseases, which are a leading cause of
death across the world. Early diagnosis and
prognosis prediction are keys for treatment
and reduction of death rates. Circular RNAs
(circRNAs) play a critical role in the physiol-
ogy and pathology of biological system and
participate in the development of diseases. In
addition, circRNAs are relative stable and
abundant. Therefore, many studies have sug-
gested that circRNAs could be used as bio-
markers for diseases, such as neurological
diseases, cancers, immune diseases, and
Q. Zhou
Shanghai Applied Radiation Institute, School of
Environmental and Chemical Engineering, Shanghai
University, Shanghai, China
Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, School of Life Science,
Shanghai University, Shanghai, China
Shanghai Key Laboratory of Bio-Energy Crops,
School of Life Sciences, Shanghai University,
Shanghai, China
© Springer Nature Singapore Pte Ltd. 2018
J. Xiao (ed.), Circular RNAs, Advances in Experimental Medicine and Biology 1087,
https://doi.org/10.1007/978-981-13-1426-1_13
13
digestive diseases. Here we summarize recent
studies on circRNAs and compare the charac-
teristics of circRNAs with traditional bio-
markers. Finally, we highlight the value of
circRNAs as potential biomarkers for cardio-
vascular diseases, including acute myocardial
infarction, heart failure, coronary artery dis-
ease, and hypertension. In conclusion, cir-
cRNAs may be promising biomarkers for
cardiovascular diseases.
Keywords
Circular RNA · Biomarkers · Cardiovascular
diseases
Z. Zhang · Y. Bei · T. Wang (*)
Cardiac Regeneration and Ageing Lab, Institute of
Cardiovascular Sciences, School of Life Science,
Shanghai University, Shanghai, China
Shanghai Key Laboratory of Bio-Energy Crops,
School of Life Sciences, Shanghai University,
Shanghai, China
e-mail: wangth@shu.edu.cn
G. Li
Cardiovascular Division of the Massachusetts
General Hospital, Harvard Medical School,
Boston, MA, USA
159
160 Q. Zhou et al.

1 Introduction of Circular RNA consist of intronic sequences. Exon-intron circu-

lar RNAs consist of both exonic and intronic
Circular RNAs (circRNAs) are currently a sequences. They predominantly localize in the
research focus in the field of noncoding RNAs, nucleus and have association with the RNA poly-
including microRNAs (miRNAs), long noncod- merase II. Therefore, exon-intron circular RNAs
ing RNAs (lncRNAs), etc. [1]. Noncoding RNAs are regarded as transcriptional regulators. Three
are involved in the development of many diseases types of circRNAs share the same characteristics,
[2], including cardiovascular diseases. They are such as stable, abundant, and conservative.
recognized as regulators of gene expression.
However, in the past, circRNAs were ignored and
considered as transcriptional noise [3] or errant 3 Characteristics of circRNAs
by-products of splicing [4], owing to their unique
structure and low abundance [4]. Based on Desirable biomarkers are required to be stable
advances in bioinformatics and biotechnology, a against harsh conditions, for example, tempera-
large number of abundant and significant cir- ture variation, extreme pH, and thawing cycles
cRNAs were discovered and identified. The evi- [11, 12]. Biomarkers should have high stability in
dence is mounting that circRNAs play essential blood and other body fluids. The biggest natural
roles in various physiological and pathological enemy of RNA is RNA exonucleases (or RNase
pathways. R). CircRNAs are closed circular molecules con-
sist of covalently closed loop structure and there-
fore resistant to RNA exonucleases that solely
2 Biogenesis of circRNAs digests linear transcripts [13–17]. CircRNAs are
more stable compared to linear RNAs [18].
CircRNAs are closed circular molecules, which Furthermore, based on their stability in blood and
are distinguished from other linear RNA mole- other body fluids [19, 20], circRNAs are suitable
cules. First circRNA was found by electron biomarkers for disease diagnosis.
microscopy from RNA viruses [5]. Nowadays, Clinical trials must be properly based upon
more and more circRNAs are being identified by reliable earlier trials and sufficient preclinical
RNA sequencing and bioinformatics. Due to the studies. CircRNAs are conserved across mam-
closed loop characteristic of circRNAs, they can mals [21], including human, mouse, and rat [22,
be extracted from the ribosomal RNA and linear 23]. In hearts, RNA-Seq analysis found that
RNA molecules in total RNA. RNA sequencing plenty of circRNAs could be detected in mammal
can obtain more circRNAs from specific accumu- species: human (16427), mouse (9953), and rat
lation of circRNAs samples. The covalently (13086). Among them, about 30% (3171) were
closed loop structure of circRNAs, also called conserved between mouse and rat, and about
“back-splicing,” is formed by joining of 3′ splice 10% (1288) were conserved in all three species
site to 5′ splice site [6, 7]. There are three types of [24]. These circRNAs conserved in different spe-
circRNAs: exonic circular RNAs (ecircRNAs) cies become abundant resources of promising
[8], intronic circular RNAs (ciRNAs) [9], and candidates for biomarkers. In addition to the ben-
exon-intron circular RNAs (EIciRNAs) [10]. efits mentioned above, circRNAs have been dem-
Exonic circular RNAs have three formation onstrating specificity in expression [25].
models: lariat-driven circularization, intron Emerging evidence have confirmed thousands of
pairing-­driven circularization, and resplicing-­ the tissue-specific expression of circRNAs [26],
driven circularization. They form from exon such as the heart, brain, skin, prostate, thyroid,
back-splicing and only consist of exonic blood, or blood cell. Through biclustering algo-
sequences. The formation of circular intronic rithm, studies have already reported thousands of
RNAs mainly depends on consensus RNA motifs tissue-specific expressed circRNAs in human
and branchpoint. Circular intronic RNAs only [26]. Except for tissue-specific expression,
13  Circular RNAs as Novel Biomarkers for Cardiovascular Diseases
c­ircRNAs have specific expression in different
diseases. In cardiac development and diseases,
the expression of circRNAs is regulated [27, 28].
Through whole transcriptome sequencing, 826
putative circRNAs have been identified in human
heart with dilated cardiomyopathy patient and
hypertrophic cardiomyopathy [27]. Through
microarray expression profile assay, 63 circRNAs
were differentially expressed in mouse between
heart failure and sham group [28].
In particular, circRNAs (3841) are found
unique in different composition and cell types of
blood [14], such as plasma (51), serum (37), neu-
trophils (58), and platelets (2339). Circulating
blood markers have enormous potential to be
applied to clinical practice. Human peripheral
whole blood is an easily accessible body fluid.
Thousands of circRNAs have been detected in
blood. Except for the blood, distinct circRNAs
have also been founded in other body fluids, such
as saliva [19]. On the other hand, circRNAs have
been found enriched in exosomes [29, 30].
Exosomes are currently regarded as specific
secretory membrane vesicles and are involved in
intercellular communication. Exosomes are also
thought to be the way of transferring miRNA in
the circulatory system, which indirectly reflects
the changes of miRNAs in diseases. Serum exo-­
circRNAs may be involved in intercellular com-
munication and can be used as indicators of
diseases development. Therefore, exo-circRNAs
in the blood of patients are expected to be mark-
ers for early diagnosis. According to the charac-
teristics talked above, circRNAs are promising
new biomarkers.
4 Functions of circRNAs
As most other noncoding RNAs, most of the cir-
cRNAs do not encode proteins. But circRNAs are
involved in regulating the expression of genes
[31]. Firstly, circRNAs can adsorb some specific
miRNAs that prevent mRNA translation, func-
tioning as miRNA sponges [25, 32]. Secondly,
circRNAs can bind to RNA-associated proteins
and form RNA-protein complexes that function
161
as RNA-binding protein (RBP) sponges [33, 34].
Thirdly, circRNAs can be a regulator of tran-
scription and alternative splicing that directly
influence gene expression [35].
For all those reasons and more, circRNAs
have been reported to play important roles in
physiological and pathological processes [36–
38], such as proliferation, apoptosis, and autoph-
agy. CircRNA circHIPK3 regulates the viability
and proliferation of endothelial cell viability by
inhibiting the activity of miR-30a-3p [36].
CircRNA TTBK2 regulates the cell proliferation
and apoptosis of human glioma cells by regulat-
ing miR-217/HNF1β/Derlin-1 pathway [37].
In addition, circRNAs can play regulatory
function in diseases, such as neurological dis-
eases [39, 40], cancers [41], immune diseases
[42], aging [43], diabetes [44], digestive diseases
[45], reproductive system diseases, skin, muscles
and bones diseases, and especially cardiovascular
diseases [46, 47]. CircRNA HRCR can function
as an endogenous miR-223 sponge through
upregulation of ARC, which attenuate hypertro-
phic responses [48]. CircRNA Cdr1as can inhibit
miR-7a through upregulating PARP and SP1,
which induces myocardial apoptosis and aggra-
vates myocardial infarction injuries [49].
Furthermore, circRNAs constitute promising
new biomarkers in multiple diseases [25, 50].
CircRNA hsa_circ_0014130 is significantly
upregulated in non-small cell lung cancer
(NSCLC) tissues that may be a new biomarker of
NSCLC [51]. CircRNA hsa_circ_0004277 is
downregulated in mononuclear cells from bone
marrow of acute myeloid leukemia (AML)
patients [52]. CircRNA hsa_circ_0001649 is
downregulated in hepatocellular carcinoma
(HCC) tissues and is correlated with tumor size
and tumor embolus’s occurrence [53].
In addition to the above examples, circRNAs
have the potential to become biomarkers in many
cardiovascular diseases. Here we will briefly intro-
duce the characteristics of circRNAs by comparison
with the existing biomarkers of cardiovascular dis-
eases, which expound the value of circRNAs. Then
we will briefly summarize recent findings on cir-
cRNAs as biomarkers in cardiovascular diseases.
162
5 Biomarkers
of Cardiovascular Diseases
Cardiovascular diseases threaten human health
and have become one of the leading diseases
which causes death in the world [54]. Nowadays,
more and more risk factors are aggravating the
development and progression of cardiovascular
diseases. Early diagnosis and prognosis predic-
tion are keys for treatment and reducing mortal-
ity. There are multiple diagnostic techniques for
cardiovascular diseases, such as blood pressure
monitoring, dynamic electrocardiogram, cardio-
vascular ultrasound, magnetic resonance imag-
ing, electronic computed tomography, and so on.
These diagnostic techniques require lots of
resources and precise instruments. What’s more,
these diagnostics still cannot ensure the accurate
diagnosis of the occurrence and development of
cardiovascular diseases.
Some blood markers are commonly regarded
as sensitive biomarkers for cardiovascular dis-
eases, such as atrial natriuretic peptide (ANP),
creatine kinase (CK), myocardial band isoen-
zyme (CK-MB), and cardiac troponin (cTn) [55].
Brain natriuretic peptide (BNP) and N-terminal
portion of its prohormone (NT-proBNP) are also
used as biomarkers for cardiovascular diseases
[56]. But there are problems difficult to solve.
Firstly, the detection time is uncertain, since
markers keep changing over time and exhibit a
relative “delayed” release time [57]. Secondly,
disease degree and patient’s background are var-
ied, while these biomarkers are low in specificity
[58]. Thirdly, there are still many kinds of cardio-
vascular diseases without proper marker, such as
coronary artery disease. As a result, there remain
many challenges in the field of cardiovascular
diseases diagnosis.
There is growing evidence that noncoding
RNAs have the potential to become biomarkers
in many cardiovascular diseases. Circulating
miRNAs are suggested as suitable biomarkers for
cardiovascular diseases [59–61], including acute
myocardial infarction (miR-1, miR-133, miR-­
208, and miR-499) [62, 63]; acute coronary syn-
drome (miR-208a, miR-34a, miR-133a,
miR-499) [64, 65]; and heart failure (miR-499,
Q. Zhou et al.
miR-133, miR-423-5p, miR-126) [66–68].
However, only a few of them have been validated,
and they are necessary to prove by large-scale
clinical studies [69]. Traditional biomarkers are
also limited by low stability [70]. Therefore, cir-
cRNAs, which are stable, conservative, and spe-
cific [71, 72], might open a novel avenue.
6  ircular RNAs as Biomarkers
C
in Cardiovascular Disease
6.1 Acute Myocardial Infarction
Acute myocardial infarction is a myocardial
necrosis caused by acute and persistent ischemia.
Acute myocardial infarction can be complicated
with arrhythmia, shock, or heart failure, which is
often life-threatening. It tends to occur in patients
with coronary atherosclerosis stenosis and coro-
nary spasm. Acute myocardial infarction carries a
high mortality rate and become a global chal-
lenge [73, 74]. Reperfusion is the most common
treatment strategy for myocardial infarction
patient. This treatment strategy will cause myo-
cardial ischemia-reperfusion injury leading to
left ventricular remodeling and even heart failure.
There are some biomarkers for clinical assess-
ment of the severity, course, and prognosis of
acute myocardial infarction. Creatine kinase(CK)
and cardiac troponin(cTn) are markers for myo-
cardial injury [75–77]. In skeletal muscles and
heart muscles, creatinine kinase facilitates the
transfer of energy phosphates between outside
and inside mitochondria. The increased concen-
tration of creatine kinase in serum indicates myo-
cardial damage, such as myocardial infarction or
ischemia. But it can also be caused by vigorous
exercise or other kinds of tissue damage [78].
Cardiac troponin I and T untimely are released
into plasma when actin and myosin filaments
occur in pathologic degeneration in the heart.
Thus, cardiac troponin can be a marker in myo-
cardial infarction. But the abnormal release of
cardiac troponin can also occur in myocarditis
[75, 76], pulmonary embolism with acute right
heart overload [79], and even heart failure [80].
Therefore, new biomarkers are required.
13  Circular RNAs as Novel Biomarkers for Cardiovascular Diseases
Recently, a study observed that a circRNA
called MICRA (myocardial infarction-associated
circular RNA) is absent in peripheral blood cells,
plasma, and serum samples [81, 82]. The particu-
lar circRNA (MICRA) is formed by 874 nucleo-
tides, which is mainly derived from zinc finger
protein 609 (ZNF609) gene exon 1 [82, 83].
MICRA is associated with development of heart
failure after myocardial infarction and can be
used to predict left ventricular remodeling after
acute myocardial infarction by multivariable anal-
yses (0.83[0.69–1.01]; p  =  0.066) [81]. Lower
level of MICRA classifies patients into decreased
ejection fraction groups; and high level of MICRA
is able to predict a preserved ejection fraction at
4 months. When MICRA is included, a multivari-
able clinical model, Akaike Information Criteria,
becomes more accurate in prediction of preserved
ejection fraction at 4 months. CircRNA MICRA
is potential to become a novel biomarker in the
future prognostication strategies of acute myocar-
dial infarction [81].
In another study, circRNA MICRA was found
lower in 642 myocardial infarction patients com-
pared to 86 healthy volunteers [82]. Besides,
MICRA was significantly lower in patients who
have a low ejection fraction. In particular, both
univariate and multivariate analyses proved that
circRNA MICRA may be a strong predictor for
prognoses of myocardial infarction after
3–4  months. Collectively, circRNA MICRA is
suggested to be able to inform the risk of devel-
oping left ventricular dysfunction for myocardial
infarction patients.
6.2 Heart Failure
Heart failure is a disorder of the systolic function
and/or diastolic function of the heart [84–86].
Heart failure is not an independent disease, but a
terminal stage in the development of heart dis-
eases [87, 88]. Almost all kinds of cardiovascular
diseases can eventually lead to the occurrence of
heart failure, such as myocardial infarction, car-
diomyopathy, hemodynamic overload, myocar-
dial injury (any cause), and inflammation [89,
90]. All these diseases can lead to alterations of
163
myocardial structure and function. Heart failure
is a major cause of morbidity and mortality
worldwide [91–93], even though its molecular
mechanisms become more and more clear and a
large amount of pharmacological interventions
come to light. In current guidelines, the plasma
levels of a natriuretic peptide (such as brain natri-
uretic peptide, BNP, and N-terminal pro brain
natriuretic peptide, NT-proBNP) are important
diagnostic indicators of acute heart failure [94].
Most of biomarkers for the assessment of heart
failure are widely acknowledged and used. But
there is still limitation that circulating levels of
BNP will significantly change with the develop-
ment of acute myocardial infarction [95].
Therefore, these biomarkers cannot be used in
the management of heart failure patients, who
have a complicated disease history.
An increasing number of RNA including miR-
NAs [19, 96] and lncRNAs [83, 97, 98] have been
found with enormous potential as biomarkers for
heart failure. LncRNA LIPCAR was found
downregulated early after myocardial infarction
and meanwhile upregulated in plasma of 788
heart failure patients [97]. LncRNA NRON and
LncRNA MHRT were found upregulated in
plasma of 104 heart failure patients [99].
CircRNAs have great potential to act as bio-
marker for myocardial infarction and heart fail-
ure. By comparing the transcriptome sequencing
through bioinformatic analysis, 1163 circRNAs
were found changed in hypertrophied myocardial
tissues grouping with or without heart failure
[28]. Through analyzing by quantitative PCR, 29
upregulated and 34 downregulated circRNAs
was validated [28]. Thus, these circRNAs may be
potential biomarkers for heart failure. Besides, a
circRNA MICRA was downregulated in
decreased ejection fraction groups (heart failure).
This circRNA might become a biomarker for
both myocardial infarction and heart failure.
6.3 Coronary Artery Disease
Coronary artery disease, a big threat to heart
health, is the main cause of coronary heart
­disease, cerebral infarction, and peripheral vas-
164
cular disease. Coronary artery disease with high
morbidity and mortality pose a threat to human
health and cause burden to economies [98]. There
are some treatments for coronary artery disease,
such as medications, percutaneous coronary
intervention (PCI), and coronary artery bypass
graft surgery (CABG) [100–102]. Minimizing
the time between plaque rupture and treatment is
critical for reducing the morbidity and mortality
[103]. But the diagnosis and prognosis of coro-
nary artery disease is almost blank at present
[104, 105].
Early detection of coronary artery disease has
the potential to increase survival rates and to
improve the life quality of patients. MiR-221 and
miR-222 have been reported reduced in carotid
plaques after an acute ischemic cerebrovascular
syndrome [106]. CircR-284 possesses a miR-221
and miR-222 binding site. Therefore, circR-284
may act as a regulator on miR-221/miR-222
activity. A validation study found that miR-221 is
significantly decreased in the urgent carotid ath-
erosclerotic plaques, compared with the asymp-
tomatic control. But perhaps even more
interesting is that circR-284 has been reported to
be significantly increased in the serum of urgent
carotid atherosclerotic plaque patient [103].
Combining the expression of serum circR-284
and miR-221, the ratio of circR-284 and miR-221
was uniquely increased in the urgent group
(P  <  0.001); and this ratio was sensitive (0.76)
and specific (0.88) for detecting plaque rupture
and stroke [103]. Based on these results, the ratio
of circR-284 and miR-221 has the potential to
become a diagnostic biomarker in cardiovascular
disease for prediction of the risk of plaque
rupture.
Identified by microarray analysis, there were
2036 circRNAs in blood differentially expressed
between coronary artery disease and control,
including 376 upregulated and 1660 downregu-
lated ones [107]. Among them, a circRNA (hsa-­
circRNA11783-­ 2) was significantly
downregulated in coronary artery disease group
but also in type 2 diabetes group [107]. In a sepa-
rate set of experiments, RNA microarray showed
22 circRNAs were differentially expressed in
Q. Zhou et al.
peripheral blood, including 12 upregulated and
10 downregulated. Hsa_circ_0124644 was sig-
nificantly upregulated in coronary artery disease
group, and this circRNA was of high sensitivity
(0.867) and specificity (0.767) for coronary
artery disease [108]. Therefore, circRNAs are
prospective diagnostic biomarkers in coronary
artery disease.
6.4 Hypertension
High blood pressure (hypertension) refers to sys-
temic arterial blood pressure (systolic pressure)
and/or diastolic blood pressure increase as the
main characteristics (systolic blood pressure,
140  mmHg or higher; diastolic blood pressure,
90 mmHg or higher). Hypertension can be asso-
ciated with the function of the heart, brain, kid-
ney, and other organs or physical damage to the
clinical syndrome. Hypertension is the most
common chronic disease and the most important
risk factor for cardiovascular disease [109–111].
Profiling and bioinformatics identified 13
downregulated and 46 upregulated circRNAs in
hypertension patients [112]. Among them, four
circRNAs (hsa-circ-0000437, hsa-circ-0008139,
hsa-circ-0005870, and hsa-circ-0040809) showed
significant difference in hypertensive patients. By
further validation, hsa-circ-0005870 was con-
firmed significantly downregulated in plasma
between 49 hypertension patients (systolic blood
pressure over 150/90 mmHg) and 49 healthy (sys-
tolic blood pressure lower than 140/90 mmHg). In
addition, hsa-circ-0005870 has also been found
related to many biological processes, such as cel-
lular response to stress. Therefore, this circRNA
may be a novel biomarker for hypertension.
In human umbilical vein endothelial cells,
7388 circRNAs have been identified. Under
hypoxia in endothelial cells, circRNAs cZNF292,
cAFF1, and cDENND4C were found upregu-
lated, whereas cTHSD1 was reduced. Among
them, cZNF292 is the highest expressed with
proangiogenic activities. These circRNA may be
new therapeutic targets and endogenous bio-
markers [113].
13  Circular RNAs as Novel Biomarkers for Cardiovascular Diseases
6.5 Chronic Thromboembolic
Pulmonary Hypertension
Chronic thromboembolic pulmonary hyperten-
sion (CTEPH) is harmful to human health.
Pulmonary hypertension is caused by obstruction
of pulmonary arteries and subsequent vascular
remodeling [114–116]. Early detection of pulmo-
nary hypertension has the potential to increase
physiological function of heart and improve
prognosis [117, 118]. In the blood samples of
chronic thromboembolic pulmonary hyperten-
sion patient, 351 circRNAs showed significant
difference, including 122 upregulations and 229
downregulations [119]. Among them, circRNA
hsa_circ_0002062 can regulate 761 miRNAs,
and circRNA hsa_circ_0022342 can regulate 453
miRNAs. Through miRNAs regulation, these cir-
cRNAs may be involved in regulating the path-
ways in chronic thromboembolic pulmonary
hypertension [119–121], such as ErbB signaling
pathway. Therefore, these unique circRNAs
which are changed and involved in chronic
thromboembolic pulmonary hypertension may
be novel biomarkers for this disease.
7 Future Perspectives
Cardiovascular diseases are not only manifold
but involute. Due to the influence of heredity
[122], diet, living habit, and external environ-
ment, different people have different age of onset,
and some people do not have obvious symptoms
in their whole life. Nowadays, many people live a
stressful, chronically overloaded, unbalanced life
that cause rising morbidity and mortality. In the
Table 13.1  Circulating circular RNAs as biomarkers in cardiovascular diseases
Diseases CircRNAs
Acute myocardial infarction MICRA
Heart failure MICRA
Coronary artery disease CircR-284/miR-221
hsa_circ_0124644
Hypertension Hsa-­circ-­0005870
Chronic thromboembolic pulmonary hsa_circ_0002062
hypertension hsa_circ_0022342
165
early stages of cardiovascular diseases, the diag-
nosis of diseases is important for treatment and
prognosis. Traditional nonspecific diagnosis can-
not fulfill the needs. A novel biomarker demands
(1) noninvasiveness and safety, (2) high sensitiv-
ity and specificity, and (3) stability and
abundance.
CircRNAs are suitable biomarkers for disease
diagnosis. Firstly, circRNAs are closed circular
molecules that are resistant to RNA exonucleases
or RNase R and hence have stability in blood and
other body fluids. Secondly, many circRNAs are
reported to be conserved across mammals.
Especially, circRNAs have high sensitivity and
specificity. CircRNAs can be source for search-
ing new therapeutic targets and candidates in dis-
ease diagnosis [123]. Multiple studies have
suggested that circRNAs may become potential
biomarkers for many cardiovascular diseases,
such as heart failure, acute myocardial infarction,
coronary artery disease, and hypertension
(Table 13.1).
There needs to be more research on explora-
tion of circRNAs as potential biomarkers. In
experimental design, patients’ physiological con-
ditions need to be more explicit, including crite-
ria such as ages, genders, colors, diet habits, and
so on. There are some details we should consider:
(1) What kind of sample can be collected, blood
sample, serum, or plasma? (2) What can be used
for normalization, Cel-mirR-39, GAPDH, or
SF3a1? (3) Which test method can be use, SYBR
or TaqMan real-time quantitative?
It is important to make strict screening crite-
ria. Although many studies assume that circRNAs
have high stability, there are some conditions that
need to be investigated, such as sample collection
Regulation Normalization Sample Ref
Down SF3a1 Blood [81, 82]
Down SF3a1 Blood [81, 82]
Up – Serum [103]
Up GAPDH Blood [108]
Down GAPDH Plasma [112]
Down – Blood [119]
Down – Blood [119]
166 Q. Zhou et al.

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