Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage
Wang et al. Clinical Epigenetics
Circulating microRNAs as potential cancer biomarkers: the advantage and disadvantage
Hao Wang 0
Ran Peng 1
Junjie Wang 1
Zelian Qin 0
Lixiang Xue 0 1
0 Medical Research Center, Peking University Third Hospital , Beijing , China
1 Department of Radiation Oncology, Peking University Third Hospital , Beijing , China
MicroRNAs are endogenous single-stranded non-coding small RNA molecules that can be secreted into the circulation and exist stably. They usually exhibit aberrant expression under different physiological and pathological conditions. Recently, differentially expressed circulating microRNAs were focused on as potential biomarkers for cancer screening. We herein review the role of circulating microRNAs for cancer diagnosis, tumor subtype classification, chemo- or radio-resistance monitoring, and outcome prognosis. Moreover, circulating microRNAs still have several issues hindering their reliability for the practical clinical application. Future studies need to elucidate further potential application of circulating microRNAs as specific and sensitive markers for clinical diagnosis or prognosis in cancers.
Cancer; Circulating microRNA; Biomarker; Diagnosis; Prognosis
Cancer is one of the leading causes of death worldwide.
In recent years, some significant improvements have
been made in tumor diagnosis and treatment. However,
early detection is still critical for improving outcomes
and reducing recurrence and mortality of cancer
patients. The absence of obvious symptoms and
insufficiently sensitive biomarkers in early stages of carcinoma
limits early diagnosis. Biopsy and imaging examination
as golden standards greatly improve the detection rate,
but their applications are limited by their own invasive
or radiation-related characteristics, respectively. In
addition, traditional tumor diagnostic markers like
carcinoembryonic antigen (CEA) and CA199 usually exhibit
low sensitivity. Therefore, it is urgent to identify novel,
more sensitive, and easy-to-detect biomarkers which can
be used in diagnosis and prognosis of cancers.
Novel methods are currently under development for
cancer detection, including those based on the detection
of microRNAs (miRNAs). MicroRNAs are endogenous,
single-stranded, non-coding small RNA with length of ~
22 nucleotide (nt). The first miRNA was discovered in
1993 in Caenorhabditis elegans which participated in
embryo development [
]. In the next two decades,
miRNAs were found in plants, animals, protists, and viruses
but not in bacteria. These small RNA molecules function
as antisense RNA to negatively regulate their target
genes at the post-transcription level. Most miRNAs have
only modest effects on the translation of their target
genes, but they constitute highly complex networks with
their targets and downstream effectors [
]. A single gene
is simultaneously targeted by multiple miRNAs, while
each miRNA is able to target numerous genes via similar
seed sequence. It was reported that miRNAs regulated
more than 30% of the human genome and are involved
in almost all fundamental cell processes [
]. A group
of target genes may function through a common
signaling pathway and accordingly facilitate similar cell
behaviors, such as proliferation, apoptosis, differentiation,
migration, invasion, metabolism, and stress response.
The expression patterns of miRNAs are usually altered
in different development stages and various pathology
conditions like senescence, cardiovascular diseases, and
2, 5, 6
]. Dysregulations of miRNAs were often
observed in different kinds of cancers due to dysfunction
of the miRNA biogenesis process, transcription of
miRNA-encoding genes, and regulator of mature
miRNAs like circular-RNA [
]. Some of these altered
miRNAs were significantly overexpressed and regarded as
oncogenes or “oncomiRs” which accelerate tumor
occurrence, development, and metastasis. Meanwhile, those
that decreased in cancer patients were considered tumor
]. The differential expression of
miRNAs can be detected by polymerase chain reaction
(PCR), Northern blotting, microarray, and deep
sequencing and have potential for clinical applications [
miRNAs in different cell types can be secreted into the
extracellular space and then transported to the
circulating body fluid like peripheral blood. It was reported that
10% of the known human miRNAs could be detected in
plasma. About 30% of them were mirtrons, rare miRNAs
originated from short-chain, hairpin-structured introns
of mRNA and through a special biogenesis pathway [
]. These miRNAs are detectable in plasma or serum in
a remarkably stable form, encapsulated into the
extracellular vesicles or bound with special lipid proteins, thus
being resistant to RNase digestions [
these small molecules are capable to be ideal candidates
to serve as biomarkers for cancer detection by liquid
biopsies. Besides peripheral blood, various body fluids,
including saliva, cerebrospinal fluid, ascites, urine, breast
milk, and semen, allow for miRNA detection .
This review mainly discussed the potential application
of circulating miRNAs as clinical cancer biomarkers. We
herein are more focused on those cancers with higher
incidence rates and mortalities, more difficult detection
in early stages, and heavier burdens on people and
society, like cancers of the lung, liver, colorectal, stomach,
Potential clinical application of circulating miRNAs
The differential expression of circulating miRNAs
exhibited promising potential for cancer screening without
additional injury for patients. The abnormal levels of distinct
miRNAs could be observed at an early stage, during
progression, and after metastasis of cancers. Thus, these small
RNA molecules may function as favorable clinical
biomarkers for distinguishing tumors, treatment strategy
selection, and outcomes. In non-small cell lung cancers
(NSCLC) patients, for example, a large group of miRNAs
have been identified to be differentially expressed in
different stages of disease and to contribute to the diagnosis,
treatment determination, and prognosis (Fig. 1).
Circulating miRNAs as biomarkers for early diagnosis
A growing number of circulating miRNAs was reported
to be dysregulated in the early stage of cancers. The
altered expression may be observed before the obvious
clinical symptoms or clear biopsy and image
examination evidence. Plasma miR-21-5p, miR-20a-5p,
miR141-3p, miR-145-5p, miR-155-5p, and miR-223-3p
significantly increased for NSCLC patients at stages I
and II [
]. Serum miR-126-3p, miR-182-5p,
miR183-5p, and miR-210-3p were also found to possess early
detective value for NSCLC patients, exhibiting similar
sensitivity and specificity with traditional tumor marker
]. Two miRNA precursors, pri-miR-944 and
primiR-3662, were also capable of distinguishing NSCLC at
stages I–IIIA [
]. Significantly decreased levels of
miR125a-3p were observed in plasma exosomes of colon
cancer patients [
], as well as increased levels of
miR23a-3p, miR-27a-3p, miR-142-5p, and miR-376c-3p in
]. A group of miRNA, including miR-642b-3p,
miR-1202-5p, miR-1207-5p, miR-1225-5p, miR-4270-5p,
and miR-4281-3p, was upregulated in plasma of breast
cancer patients with stage I [
]. Serum miR-1825-3p
was specifically downregulated in glioma at early stage,
and its level was correlated with tumor progression and
poor prognosis [
]. These evidences suggest that the
circulating miRNA detection might be introduced for
early-stage cancer screening.
Circulating miRNAs as diagnosis biomarkers to distinguish different subtypes of cancer
Cancers can be divided into different subtypes by tissue
origination or pathological mechanisms. For example,
NSCLCs include two major pathologic subtypes,
adenocarcinoma (ADC) and squamous cell carcinoma (SCC)
]. Breast cancers are well known as heterogeneous
diseases, which can be sub-classified by the presence of
estrogen receptor (ER), progesterone receptor (PR), and
HER2/neu receptor [
]. The sub-classification of
specific tumors is valuable for determining tumor
mechanisms and making therapeutic decisions. Of note,
certain differentially expressed miRNAs in parallel with the
different subtypes draw more and more attention
recently. They could be optimal to determine tumor
subtype and pathology, contributing to the selection for a
more efficient therapeutic approach.
Taking NSCLC as an example, the accurate
subclassification into ADC and SCC is important for
deciding treatment methods. Expression patterns of
several miRNAs were different not only between the
plasma of NSCLC patients and healthy individuals, but
also between ADC and SCC patients. Levels of
miR-165p and miR-486-5p were elevated in ADC and SCC
cases compared to those of healthy ones. miR-9-5p
expression was stable between overall NSCLC patients
and healthy controls, but exhibited significant
declination in ADC patients instead of SCC ones. Another
plasma miRNA, miR-205-5p, was upregulated only in
SCC patients [
]. Additionally, Jin et al. found several
ADC- and SCC-specific differentially expressed
miRNAs by RNA sequencing [
miR-3615p, and miR-320b were significantly elevated in plasma
exosomes of NSCLC patients. The levels of miR-181-5p
and miR-361-5p were increased by more than 10 times
in ADC patients than SCC patients, and miR-320b in
SCC samples increased by over 10 times than in ADC
ones. miR-30a-3p and miR-30e-3p were specifically
downregulated in ADC patients, while miR-10b-5p and
miR-15b-5p were decreased in SCC patients. Therefore,
investigators suggest that these miRNA panels may be
not only applicable in NSCLC diagnosis, but also
helpful to subtype discrimination. Interestingly, cell-free
miRNA precursors were also found to have diagnostic
potential. Pri-miR-944 was suggested to distinguish
SCC from ADC, while pri-miR-3662 distinguished
ADC from SCC [
]. In addition, the mature forms of
these two miRNAs were also revealed to have the
potential in indicating the diagnostic accuracy for
operable SCC and ADC, respectively [
The subtyping of heterogeneous breast cancer is also
of great importance for clinical therapy. The positively
expressed ER, PR, or HER2/neu in tumors could be
directed as therapeutic targets. On the contrary, patients
bearing triple-negative breast cancer (TNBC), which
expressed none of these receptors, were usually treated
with traditional chemotherapy or radiotherapy [
TNBC was associated with higher stage at diagnosis and
poorer prognosis. Therefore, biomarkers of specific
breast cancer subtypes have also been focused on,
especially for TNBC from the miRNA point of view. Shin et
] observed the declined levels of miR-16-5p,
miR21-5p, and miR-199a-5p in plasma and tumor tissues of
TNBC patients compared with both non-TNBC and
healthy individuals, as well as the elevated levels of
miR92a-3p and miR-342-3p. Among them, miR-199a-5p
exhibited the highest value to distinguished TNBC from
non-TNBC. This small molecule was validated to be
downregulated since the stage I of tumor and to
decrease with tumor progression [
exosomal levels of miR-373-3p were increased in TNBC but
not luminal carcinomas and higher in ER/PR-negative
tumors than receptor-positive tumors [
serum levels of miR-373-3p showed no significant
difference between TNBC and luminal carcinomas.
In other cancers, different tumor subtypes may also be
distinguished by circulating miRNAs. Exosomal levels of
miR-101-3p and miR-483-5p in plasma of adrenocortical
cancer were significantly higher than those of
adrenocortical adenomas, which could be adopted to preoperative
diagnosis of adrenocortical malignancy [
]. On the
other hand, papillary and follicular thyroid cancer might
be distinguished by the expression of exosomal
miR-215p, miR-31-5p, and miR-181a-5p in combination [
Circulating miRNAs contribute to monitor tumor metastasis
The occurrence of tumor metastasis leads to a
significant impairment of curative effect, resulting to the poor
survival rate and high risk of recurrence. There are
currently no reliable biomarkers for predicting metastatic
spread to different sites. According to the characteristics
of relative tissue specificity of miRNAs, the candidates
for this purpose become favorable since more and more
circulating miRNAs were found to be associated with
clinical tumor stage and/or metastasis. In osteosarcoma
patients, miR-497-5p was significantly downregulated in
primary tumor tissues, metastatic tissues, and serum
compared to healthy controls [
]. This small
molecule targeted multiple genes like IGF-1R , VEGFA
], AMOT [
], and P21 [
] to inhibit osteosarcoma
cell proliferation, migration, and invasion and enhance
apoptosis. Furthermore, the declined miR-497-5p
expression was associated with clinical stage, distant
metastasis, and promoted cisplatin resistance [
Elevated levels of miR-205-5p in plasma were correlated
with tumor stage and pathological grade in patients with
bladder cancer . miR-148a-3p expression was
reduced in plasma of ovarian cancer patients and
correlated with histopathologic grade and lymph node
]. Plasma levels of miR-520g were higher
in breast cancer patients with low differentiation degree
grade, mammary gland invasion, and lymph node
]. Additionally, both miR-106a-5p and
miR196a/b-3p were upregulated in gastric cancer patients,
and their levels were associated with TNM stage and
metastatic potential [
]. In the future, further
clarifying the miRNAs from the original tumor sites or the
targeted metastatic tissue/organ might be helpful to
predict the upcoming metastasis event.
Circulating miRNAs predicted the sensitivity of tumor to clinical treatment
Chemotherapy and radiotherapy are important
approaches for tumor treatment, which are often in
combination with surgical operation. However, some types of
tumor cells may gain resistance after long-time treatment
due to the heterogeneity of tumors. As a result, parts of
patients would have worse outcomes upon a certain
treatment. Investigators expect to find accurate biomarkers to
detect or predict the resistance of different cancers, in
order to select superior treatment strategies.
In pancreatic ductal adenocarcinoma (PDAC), a main
subtype of pancreatic cancer, miR-155-5p was
upregulated in tumor tissues and plasma, and the expressions
in tissues were associated with tumor stage and poor
]. Besides, long-term administration of
gemcitabine in tumor cells further overexpressed
miR155-5p which was released into exosomes to induce
gemcitabine resistance via anti-apoptotic activity.
Therefore, higher miR-155-5p expression showed
chemoresistance and poor prognosis for PDAC patients receiving
gemcitabine treatment [
]. Levels of miR-1914-3p and
miR-1915-3p in plasma from chemo-resistant colorectal
cancer (CRC) patients were decreased compared to
those from responders. These two miRNAs were
demonstrated to facilitate cell resistance to 5-Fu and
oxaliplatin by NFIX in vitro [
]. Aberrant reduction of
miR497-5p in plasma of osteosarcoma patients implied the
poor response to chemotherapy [
]. Furthermore, lower
miR-146-5p levels in serum exosomes were associated
with the cisplatin resistance and shorter progression-free
survival (PFS) for NSCLC patients [
]. These putative
resistant miRNAs may be favorable for monitoring the
resistant and tolerance of treatment and for selection of
clinical therapeutic approach. In line with these findings,
targeting those miRNAs and their downstream targets
might become the novel strategy to rescue the resistance
against chemotherapy or radiotherapy.
Circulating miRNAs as prognostic biomarkers of cancers
Accumulating evidences suggested that circulating levels
of miRNAs may be associated with the outcomes. The
expressions of miR-222-3p in serum exosomes were
associated with poor outcomes of NSCLC patients [
internalized via caveolin- and lipid raft-mediated
endocytosis, miR-222-3p promoted the proliferation,
chemoresistance, migration, and invasion of recipient cells.
Elevated levels of miR-23b-3p, miR-10b-3p, and
miR-215p in exosomes were associated with poor overall survival
(OS) of NSCLC patients [
]. Additionally, higher levels
of miR-21-5p and miR-4257-3p existed in exosomes of
recurrent NSCLC patients compared with those without
recurrent and the healthy controls [
]. The level of these
two exosomal miRNAs was associated with disease-free
survival (DFS), while miR-4257-3p alone was also
associated with node metastasis and TNM stage. On the other
hand, miR-21-5p was also upregulated in the circulating
exosomes, primary tumor tissues, and liver metastasis
]. Exosomal level of miR-21-5p was associated
with liver metastasis, TNM stage, and poor prognosis,
including shorter OS and DFS.
Besides the tumor type mentioned above, circulating
miRNAs also showed tight correlation with prognosis in
other types of tumors. The levels of let-7b and
miR-18a5p were significantly associated with DFS and OS in
multiple myeloma patients [
]. miR-4772-3p levels were
negatively associated with the risk of recurrence and
death in serum exosomes derived from stage II and stage
III colon cancer patients [
]. Higher levels of plasma
miR-148a were associated with longer OS in ovarian
cancer patients [
]. Lower plasma levels of
miR185-5p were correlated with poor survival in glioma
patients . These findings above suggest the promise of
applying circulating miRNAs as biomarkers for early
prediction upon certain treatment and improvement of
the outcomes in most types of cancer.
The advantage of circulating miRNAs as diagnosis and prognosis biomarkers
Traditional cancer markers are mainly produced by
tumor tissues or normal embryo tissues, while absence
or in tiny amount in tissue and blood of healthy adults.
The most validated traditional cancer markers include
alpha-fetoprotein (AFP), carcinoembryonic antigen
(CEA), and carbohydrate antigen (CA) [
]. They are
generally broad-spectrum biomarkers for diagnosis of
various types of cancers. CEA, CA199, and CA125 were
generally accepted to be validated to have positive
predictive value as circulating biomarkers for different
cancers. Other screening strategies include mammography
for breast cancer [
], colonoscopy for CRC [
and prostate-specific antigen (PSA) for prostate cancer
]. However, still missing are more effective, accurate,
specific, and sensitive screening biomarkers to fulfill the
detective and predictive functions in the care of cancer
patients. Circulating miRNAs have the particular
advantage as a potential clinical application.
Circulating miRNAs are non-invasive biomarkers
Circulating miRNAs are easy to obtain without severe
damage. Besides, a great number of potential effective miRNA
biomarkers are stable in healthy people. Their expression
levels may not be obviously affected by age, gender, body
mass index (BMI), smoking status, or other basic
characteristics when evaluating pathogenic potential. Hence, the
altered expression pattern might be introduced to routine
examination for monitoring and early diagnosis of cancers.
Although cell-free miRNAs from plasma and serum are
the most common circulating miRNA biomarkers, other
body fluid samples like urine and saliva are also applicable
as the resource of circulating miRNAs. miR-186-5p was
overexpressed in not only tumor tissues and blood, but also
urine from bladder cancer patients [
]. Several miRNAs
including miR-210-3p were upregulated in urine from
transitional cell carcinoma patients and capable to facilitate
cancer diagnosis [
]. All members of let-7 families were
significantly elevated in urine from clear-cell renal cell
cancer (ccRCC) patients [
], while a combination of
urinary exosomal miR-34b-5p, miR-126-3p, and miR-449a-3p
could be favorable for ccRCC diagnosis [
]. A panel of
four breast cancer-related miRNAs (miR-21-5p,
miR-125b5p, miR-155-5p, and miR-451-5p) was also differentially
expressed in urine samples of breast cancer patients and
exhibited their diagnostic value [
]. Elevated levels of
miR143-3p and miR-30e-5p in urine samples of PDAC patients
shown their potential as diagnostic biomarkers in the early
]. Therefore, these easily accessible cell-free small
molecules have been widely applied for clinical use.
Circulating miRNAs may be used for screening tumors with higher sensitivity
Up to now, polymerase chain reaction (PCR) is still the
major examination technology for circulating miRNA.
Amplification is a critical step and characteristic of all
kinds of PCR, which magnifies the initial difference
between samples, even if the difference is quite small.
Therefore, the current detection method makes
circulating miRNAs more sensitive biomarkers. Monitoring of
the aberrant expression can be easier and earlier
compared with biopsy and/or image examination which
reflects the actual size without amplification, although the
latter are regarded as the golden standard so far.
The dynamic expression pattern of circulating miRNAs may be associated with the progression of tumors
The generation of miRNAs is dynamic and prompt upon
the internal or external stimuli. This feature endows
miRNAs the ability to observe the whole time course
changes in real time and dynamic manner from
tumorigenesis throughout the following progression.
miR-1955p was reported to inhibit the proliferation, migration,
and invasion of NSCLC cells via multiple targets [
], and the lower miR-195-5p levels in plasma were
showed to be associated with lymph node metastasis
and advanced clinical stage . Serum miR-373-3p was
downregulated in pancreatic cancer patients, and
miR373-3p level was negatively correlated with TNM stage,
lymph node metastasis, and distant metastasis [
periampullary carcinoma, miR-192-5p levels were
increased and correlated with tumor stage and
]. A panel of miRNAs including
miR34a-5p, miR-34b-5p, and miR-34c-5p was significantly
downregulated in TNBC patients. Among these miRNAs,
miR-34a-5p expression was positively correlated with
lymph node metastasis together with miR-34b-5p and
correlated with tumor grade and distant metastasis together
with miR-34c-5p [
]. These observations revealed the
possibility of circulating miRNAs for evaluating the stage
and progression of tumors. The whole dynamic expression
pattern of miRNAs could depict the development
landscape of cancer during the entire progression.
The disadvantage and limitation of circulating miRNAs as diagnosis and prognosis biomarkers
The diversified origin of circulating miRNAs influences the effectiveness partially
Most of potential miRNA biomarkers ubiquitously exist
in both healthy individuals and cancer patients. The
differences in their expression levels between healthy
people and patients are usually quite tiny. So the way of
sampling cannot be ignored to distinguish cancers from
healthy state or other benign injury accurately.
Currently circulating miRNAs are obtained from
venous plasma or serum. miRNA profiles in venous and
arterial plasma were largely similar, so the levels of most
miRNAs have no significant difference between vein and
artery. Five elevated miRNAs (miR-20b-3p, miR-28-3p,
miR-192-5p, miR-223-3p, and miR-296-5p) were
identified from serum of esophageal squamous cell carcinoma
(ESCC) patients [
]. The investigators compared their
content in venous and arterial serum and found no
statistic difference. However, the use of venous miRNAs for
cancer detection was still challenged in some cases. Ten
arterial highly expressed miRNAs and fourteen venous
highly expressed miRNAs were identified in plasma
samples of healthy male rats [
]. The miRNA profiles in
arterial plasma showed higher correlation with that in
tissue. Studies with human samples had similar
observations. Levels of upregulated miRNAs (miR-10-3p,
miR21-5p, miR-409-3p, and miR-425-5p) were even higher
in arterial plasma compared with venous plasma from
lung adenocarcinoma patients [
]. Levels of let-7g-5p,
miR-15b-5p, miR-155-5p, and miR-328-5p were found
to be significantly higher in mesenteric vein than in
peripheral vein and tumor tissue from colon cancer
patients, suggesting that tumor drain vein contained
more complete biomarkers origin from tumor tissues
than peripheral vein [
]. Thus, the blood sampling
methods should be carefully considered for some
specific miRNA biomarkers.
Exosomal miRNAs in peripheral blood have also
drawn more and more attention in the aspect of
biomarkers. It is known that most of the miRNAs in blood
were packaged in extracellular vesicles like microvesicles
and exosomes. Several miRNAs were reported to
differently express in plasma, serum, and peripheral blood
exosomes. For example, miR-181b-5p and miR-21-5p
were enriched in the exosomes of lung cancer patients
instead of healthy individuals [
]. Plasma levels of
miR19b-3p, miR-21-5p, miR-221-3p, miR-409-3p,
miR-4255p, and miR-584-5p were elevated in lung
adenocarcinoma patients, but only miR-19-3p, miR-21-5p, and
miR221-3p were found to be upregulated in plasma
]. Similarly, a panel of five serum miRNAs
overexpressed in ESCC patients, including miR-20b-5p,
miR-28-3p, miR-192-5p, miR-223-3p, and miR-296-5p.
Only miR-296-5p was found to be upregulated in ESCC
serum exosomes [
]. Likewise, miR-132-3p and
miR185-5p were overexpressed in gastric cancer patients’
serum instead of exosomes [
]. miR-101-3p was
elevated both in serum and exosomes from breast cancer
patient, but expression levels of miR-372-3p and
miR373-3p increased in exosome and serum, respectively
]. These observations implied the importance of
selecting a proper sampling method for certain
Single miRNA molecule has limitations in both sensitivity and specificity
High sensitivity and specification are the fundamental
demands and the most important evaluation criteria for
circulating miRNAs as diagnostic or prognostic biomarkers
for clinical application. Single miRNA molecules could
hardly meet the criteria for many candidate miRNA
biomarkers because their levels in patients and healthy
controls were overlapped. This observation suggested that the
level of an applicable miRNA biomarker should possess
high individual difference, which increased the possibility
of false negative or positive diagnosis.
On the other hand, many cell-free miRNAs showed
altered expression patterns in various types of cancers
instead of a certain cancer type. miR-21-5p, miR-155-5p,
and miR-210-3p are good examples, as all of them are
involved in cancers like NSCLC [
], and colorectal cancer [
57, 93, 94
Additionally, there was similar expression between
benign injury and malign tumor. miR-21-5p levels in
plasma significantly increased in CRC patients, but this
candidate biomarker could not distinguish the
carcinoma and benign polyps . Therefore, there should be
a strict process of screening from bench to bedside.
Therefore, a larger sample size was essential to obtain
the basal line of candidate of interest and decide
whether it could clearly separate the health and disease
status. Only those who have high sensitivity and
specificity in people with different characteristics have the
potential for clinical application (Fig. 2). In addition, more
advanced technologies like digital PCR were developed
in last years. These advanced methods could be further
appropriate to overcome these difficulties.
Contribution of miRNAs in different cancers is
complicated. A certain miRNA can be oncomiR in this kind
of tumor and suppressor in another. Circulating
miR-215p was reported to be upregulated in patients of NSCLC
17–19, 55, 56, 72
], liver cancer , and gastric cancer
], but downregulated in patients suffered from
breast cancer [
]. The levels of miR-195 in
peripheral blood were lower in patients with hepatocellular
] and cervical cancer [
]. On the
contrary, its increased plasma levels were observed in
osteosarcoma patients [
] and associated with poor
prognosis of head and neck cancer patients [
]. It was
of great importance for careful assessment when
discussing the clinical application value for the certain miRNA
molecules in a certain tumor.
Recently, more and more investigators turned to
incorporate several miRNAs to improve the diagnostic
Fig. 2 Screening for potential circulating miRNA biomarkers for clinical
applications. A great number of differentially expressed miRNAs were
identified in laboratory investigations to constitute the candidate pool.
In the further screening, candidates which had no correlation with
individual characteristics were retained, as well as those with high
specificity and sensitivity in order to distinguish cancer patients from
healthy people accurately. They were considered as potential clinical
biomarkers for large-scale validation
effect or combine miRNAs with traditional biomarkers
like CEA. Several panels of miRNAs were already
introduced to ESCC detection [
]. Plasma levels of miRNA
pair miR-19b-3b and miR-297-5p were found to be
diagnostically significant for prostate cancer [
combination of exosomal miR-126-3p, miR-449a-5p, and
miR-34b-5p was adopted to the diagnosis of ccRCC, and
combination of miR-126-3p and miR-34b-5p could
identify carcinoma and benign injury [
]. It appears that the
combination of different miRNAs or miRNAs with other
clinical indicators will be the tendency for precise cancer
detection in the future.
A growing number of circulating miRNAs were found to
have potential to act as diagnostic or prognostic
biomarkers for various types of cancer patients, especially
for long-term, slow progress solid tumors which are
hard to detect at early stage. However, the difference
between criteria of scientific research and clinical
application is quite obvious. This gap makes it important to
carefully examine for any potential miRNA biomarkers.
An appropriate applicable biomarker for specific cancer
should not only be significantly differentially expressed,
but also be capable of defining the correlation with the
outcome of patients.
The limited sample size was another unavoidable
obstacle. In practical clinical application, the level of
circulating biomarkers would be under the influence of
multiple individual classifications, including age, gender,
ethnic, lifestyle, history of diseases, and so on. Although
many investigators validated that the miRNAs they
focused were not affected by individual characteristics, the
proportion may be limited, and larger sample size cohort
studies were still needed for further assessment.
Detection results could also be affected by measurement
principle, method, instrument, and the operation of
technicians. So expanding the sample size could be a
critical process to ensure the accuracy for cancer
diagnosis. In addition, the absolute quantitative detection
method may be promising as well as a basic level of the
circulating biomarker in healthy controls.
Differentially expressed circulating miRNAs may also
play other roles for patients suffering from different
cancers except for functioning as biomarkers. Some of them
may be just results or by-products of diseases, and the
others participated in the occurrence and development
of tumors directly or indirectly. There are few studies to
reveal the association between the levels of aberrant
expressions of miRNAs and therapeutic options so far.
However, those miRNAs that participated in tumor
pathology may reflect and in turn change the cellular
transcriptome via complex regulatory network.
Exogenous overexpression or inhibition of those functional
miRNAs would probably rescue the pathological
development and do favor to the treatment and improvement.
Therefore, the circulating miRNA biomarkers could
further serve as valuable research targets and candidate
small molecule drugs for clinical treatment.
So far, multiple independent validation studies are still
demanded for clinical application. The combination of
miRNAs with other biomarkers and precise selection of
their origin could contribute to further researches.
Obtaining the comprehensive view of miRNAs,
identified and unidentified, as well as the lncRNAs,
circularRNAs, and other ncRNAs is still on the way. With
clearer regulatory guidance, a more precise approach
could be expected to provide a promising detection to
improve treatment outcomes.
In conclusion, circulating miRNAs exhibited promising
potential to serve as effective non-invasive cancer
biomarkers for clinical application. They may be valuable in
various aspects including cancer screening in the early
stage, subtype classification and drug sensitivity
prediction for treatment strategy selection, and screening the
chemo- or radio-resistance of tumors to prognosis the
outcomes and recurrences. Larger scale studies are
expected to further promote the sensitivity, specificity, and
applicability of potential circulating miRNA biomarkers
in the future.
ADC: Adenocarcinoma; AFP: Alpha-fetoprotein; BMI: Body mass index;
CA: Carbohydrate antigen; ccRCC: Clear-cell renal cell cancer;
CEA: Carcinoembryonic antigen; CRC: Colorectal cancer; DFS: Disease-free
survival; ER: Estrogen receptor; ESCC: Esophageal squamous cell carcinoma;
miRNA: MicroRNA; NSCLC: Non-small cell lung cancers; OS: Overall survival;
PCR: Polymerase chain reaction; PDAC: Pancreatic ductal adenocarcinoma;
PR: Progesterone receptor; PSA: Prostate-specific antigen; SCC: Squamous cell
carcinoma; TNBC: Triple-negative breast cancers
We appreciate the valuable comments from Prof. Qinghua Cui in Peking
University Health Science Center and the kindly linguistic assistance from
Qiaochu Zhang from Dep. Bioengineering and Biomedical engineering in
Rice University, Houston, Texas.
This work was supported by grants from the National Natural Science Foundation
of China (NSFC No.91749107, No.81672091) and Beijing Natural Science
Foundation (BJNSF No. 7172232).
HW, RP, and JW acquired the materials and wrote the manuscript draft. ZQ
and LX designed the drafting and reviewed and edited the manuscript. All
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