REVIEW

CURRENT
OPINION Circulating microRNAs in adrenal tumors
Peter Igaz a,b

Purpose of review
Circulating microRNAs represent promising minimally invasive markers of several diseases including
tumors. As the preoperative diagnosis of different adrenal tumors is difficult, for example, diagnosis of
adrenocortical or adrenomedullary malignancy, circulating microRNAs might be helpful in their clinical
management.
Recent findings
Observations regarding the applicability of circulating microRNAs isolated both from unfractionated
plasma or serum and from extracellular vesicle preparations for the diagnosis of adrenocortical malignancy
have been published. Data show that circulating microRNA might be exploited for monitoring
adrenocortical cancer progression. Circulating microRNA profiles of adrenal myelolipoma have also been
published that might be useful for differentiating adrenocortical cancer and adrenal myelolipoma in
dubious cases.
Summary
In this review, recent advances in the field of circulating microRNAs in adrenal tumors are discussed.
Keywords
adenoma, adrenocortical, cancer, circulating, microRNA, myelolipoma, pheochromocytoma

INTRODUCTION
MicroRNAs (miRNA), the endogenous mediators of
RNA interference as parts of the epigenetic machin-
ery are involved in the regulation of several basic
cellular processes and alterations in their expression
have been described in several diseases including
tumors [1,2]. MiRNA are encoded by separate genes
and undergo a sophisticated maturation process
taking place both in the cellular nucleus and the
cytoplasm leading to mature, single-stranded
miRNA of 19–25 nucleotides that are able to specifi-
cally bind the 50 untranslated region of their mRNA
targets. The biological activity of miRNA is redun-
dant, as the same mRNA can be bound by different
miRNA that often act in a synergistic manner, more-
over they are pleiotropic having several mRNA tar-
gets [1]. Beside their ‘classical’ posttranscriptional
cytoplasmic actions, numerous findings underline
their nuclear activities influencing gene expression
[2]. The expression of miRNA is tissue specific and
the same miRNA can be oncogenic or tumor sup-
pressor in different tissues [3].
Several tissue miRNAs have been shown to be
promising biomarkers of malignancy that are espe-
cially useful for tumors whose histological analysis
is difficult. Overexpressed miRNA in tumors are
considered as oncogenes (oncomiR), whereas under-
expressed are tumor suppressors [4]. Findings from
the past decade have shown that miRNA can also be
found in body fluids (e.g., blood, urine, and milk)
[5,6], whereas tissue miRNA of solid tumors can be
analyzed either from biopsy samples or from surgi-
cally removed tumors; circulating miRNA can be
exploited as minimally invasive markers belonging
to liquid biopsy.
Tissue miRNA can be released in body fluids via
passive release (inflammation or necrosis) or via
active secretion. Actively secreted miRNA are either
packed in extracellular membrane vesicles (exo-
somes, microvesicles, or apoptotic bodies) or in
macromolecular complexes [Argonaute 2 protein
(Ago2) and high-density lipoprotein] [7]. Circulat-
ing miRNA in extracellular vesicles or bound to high
density lipoprotein have been shown to be trans-
ferred to different cells, thus circulating miRNA
a
2nd Department of Internal Medicine, Faculty of Medicine and bMTA-SE
Molecular Medicine Research Group, Hungarian Academy of Sciences,
Semmelweis University, Budapest, Hungary
Correspondence to Peter Igaz, MD, MSc, PhD, DSc, 2nd Department of
Internal Medicine, Faculty of Medicine, Semmelweis University, H-1088
Budapest, Szentkirályi Str. 46, Hungary; Mailing Address: H-1085 Buda-
pest, Üllői Str. 26, Hungary. Tel: +36 1 4591500; fax: +36 1 2660816;
e-mail: igaz.peter@med.semmelweis-univ.hu
Curr Opin Endocrinol Diabetes Obes 2019, 26:155–159
DOI:10.1097/MED.0000000000000472

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Adrenal cortex and medulla
KEY POINTS
 Circulating miRNAs display promising diagnostic
accuracy for differentiating benign and malignant
adrenocortical tumors.
 Circulating miRNA might be exploited for tumor
progression monitoring of adrenocortical cancer.
 Uniform requirements for methodology on circulating
miRNA are required for introduction to clinical
medicine.
 Despite some hypotheses on their potential pathogenic
relevance, experimental evidence on the implication of
circulating miRNA in adrenal tumorigenesis and
progression is lacking.
might convey epigenetic information between dif-
ferent cells and tissues, and can be considered as
&
epigenetic ‘hormones’ [8 ]. We have raised the
hypothesis that the predominance of tumor sup-
pressor miRNA in plasma might represent a tumor
surveillance mechanism [9]. The pool of intracellu-
lar and extracellular miRNAs is often different, but
the cellular mechanisms regulating the sorting of
miRNA to be secreted are poorly understood [7].
It must be noted, however, that the analysis of
circulating miRNAs is rather difficult that is in part
related to their very low concentration (femtomolar
range for individual miRNAs) [10], different analytic
platforms, lack of standards for normalization and
reference genes (spike-in control vs. biological con-
trols), so on. [11,12]. MiRNA can be detected both in
unfractionated plasma/serum or in extracellular ves-
icle preparations. We prefer plasma for the analysis,
as blood clotting is thus avoided, and platelets repre-
sent a rich source for miRNA [12]. As extracellular
vesicles are actively secreted, it might be argued that
miRNA isolated from these could be more specific for
diseases than unfractionated plasma containing cel-
lular debris. For miRNA profiling in body fluids, next-
generation sequencing can be proposed, but for vali-
dation, real-time PCR remains the most widely used
approach. Unfortunately, there is no widely accepted
reference for normalization. Spike-in control (e.g.,
cel-miR-39 from Caenorhabditis elegans) is an exoge-
nous RNA added during the process of RNA isolation,
and thus no biological control. Biological controls
(e.g., hsa-miR-16) can also be used, for example, in our
study on unfractionated plasma samples [11], how-
ever, in our later study on extracellular vesicle prep-
&
arations it showed considerable variation [13 ].
Adrenal tumors display several peculiar features
leading to difficulties in their diagnosis. The histologi-
cal diagnosis of malignancy in adrenocortical tumors
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requires great expertise [14], and it is impossible in
pheochromocytomas (PHEO) in which malignancy
can only be established by clinical criteria, that is,
presence of metastases [15]. The preoperative diagnosis
of adrenocortical malignancy mostly relies on imaging
and hormonal features, but unfortunately there is no
available blood-borne marker of malignancy at pres-
ent. Urinary steroid metabolomics is a very promising
novel approach for the diagnosis of adrenocortical
malignancy [16], but it is not widely available, whereas
the histological diagnosis of adrenal myelolipoma
(AML) is easy, its preoperative diagnosis might rarely
be difficult, for example, if the proportion of bone
marrow componentsis higher and thus even enhanced
18
F-fluorodeoxyglucose uptake at PET-CT might be
observed [17]. Both advanced malignant adrenocorti-
cal and adrenomedullary tumors have dismal progno-
sis, and there are no reliable markers of disease
progression [14,15]. Circulating miRNAs might be
helpful in many of these clinical settings, and there
have been some relevant findings in the field inthe past
12–18 months that are worthy of discussion.
ADRENOCORTICAL TUMORS
The clinically most relevant issue related to circulating
miRNA in adrenocortical tumors is the establishment
of malignancy. Several studies have investigated the
expression of tissue miRNAs in adrenocortical adeno-
mas (ACA) and adrenocortical cancer (ACC). Among
the most consistently overexpressed tissue miRNAs in
ACC, hsa-miR-483–5p, hsa-miR-210, and hsa-miR-503
can be highlighted, whereas hsa-miR-195 was found to
be underexpressed in ACC in several studies [18–21].
(The prefix hsa- in the name of miRNAs refers to Homo
sapiens.)
Circulating counterparts of these miRNAs have
been investigated, as well. Overexpressed serum or
plasma hsa-miR-483–5p has been found in all studies,
and thus circulating hsa-miR-483–5p can be consid-
ered the best circulating miRNA marker of ACC to
&
date [11,13 ,22,23]. In the study of Chabre et al. [23]
on unfractionated serum samples, however, hsa-miR-
483–5p was significantly overexpressed only in
aggressive relative to nonaggressive ACC. In the other
two studies using unfractionated serum [22] or
plasma [11], hsa-miR-483–5p was found to be over-
expressed in ACC relative to ACA, as well.
Among the other circulating miRNA proposed
as markers of adrenocortical malignancy, underex-
pressed hsa-miR-195 and hsa-miR-335 [23], overex-
pressed hsa-miR-100, hsa-miR-181b, hsa-miR-184,
hsa-miR-210 [11], and hsa-miR-34a [22] need to be
mentioned. We have found that the other mature
miRNA from the miR-483 locus, circulating hsa-
&
miR-483–3p is also overexpressed in ACC [24 ].
Volume 26  Number 3  June 2019
 Circulating microRNAs in adrenal tumors Igaz

Overexpressed hsa-miR-483–5p and underex- and cortisol-producing ACC relative nonfunction-

pressed hsa-miR-195 were suggested as markers for
shorter recurrence-free and overall survival, as well
[23].
It is interesting to note that despite being over-
expressed in serum, tissue hsa-miR-34a was found to
be underexpressed in ACC tissue by miRNA profiling
indicating that the expression of tissue miRNAs and
their circulating counterparts can be different [22].
It has been suggested that the release of hsa-miR-34a
by ACC cells might represent a mechanism whereby
cells can get rid of this miRNA that in part targets
p53 [25,22]. An inverse relationship between abun-
dant ACC tissue and scarce serum expression was
observed for hsa-miR-376a [23].
The diagnostic accuracy of these miRNA is vari-
able (Table 1). The highest area under curve
achieved to date was noted in our study on extra-
cellular vesicle-associated miRNA for hsa-miR-483–
&
5p [13 ], but underexpressed hsa-miR-195 displayed
a high diagnostic accuracy, as well [23]. The expres-
sion of circulating hsa-miR-483–5p is not influenced
by dynamic hormonal tests (adrenocorticotropin
and overnight dexamethasone tests) often used in
adrenal tumor diagnosis [26] that supports its appli-
cability as a diagnostic marker. Extracellular vesicle-
associated (mostly exosomal) hsa-miR-483–5p can
thus be considered to be a promising marker of
&
adrenocortical malignancy [13 ].
The expression of some circulating miRNA
seems to be associated with cortisol secretion
&
[27 ], as the expression of hsa-miR-22–3p, hsa-miR-
27a, and hsa-miR-320b is significantly increased in
both cortisol-producing adrenocortical adenomas
ing adenomas. Significant correlation of their levels
and urinary free cortisol and cortisol after low dose
&
dexamethasone tests were noted [27 ]. On the other
hand, hsa-miR-320b is overexpressed in cortisol-pro-
ducing ACC relative to cortisol-producing adreno-
&
cortical adenomas [27 ] (Table 1). The relationship
between cortisol secretion and these miRNA is, how-
ever, unclear. Glucocorticoid-responsive elements
can be predicted in these three miRNAs associated
&
to cortisol production [26,27 ]. Circulating hsa-miR-
27a is induced by dexamethasone, and inhibited by
adrenocorticotropin in vivo in humans, and it is also
induced by dexamethasone in vitro [26] confirming
the glucocorticoid responsiveness of this miRNA.
These miRNA might even be implicated in the
pathogenesis of Cushing syndrome, but experimen-
tal evidence is lacking.
A further potential application of circulating
miRNA might be disease activity monitoring that
has been investigated in two xenograft studies.
There is no available tumor marker in ACC that
would be correlated to tumor size. Circulating hsa-
miR-483–5p was found to be decreased by effective
mitotane and 9-cis retinoic acid treatment in an
NCI-H295R xenograft model [28], whereas the
major hypoxamiR hsa-miR-210 [29] was overex-
pressed by liposomal etoposide-doxorubicin-pla-
tina-mitotane chemotherapy in an SW-13
xenograft model [30]. In the human clinical setting,
&&
Salvianti et al. [31 ] developed a quantitative real-
time assay for measuring absolute levels of hsa-miR-
483 and miR-483–5p in plasma samples thus over-
coming the need for a reference gene, and have

Table 1. Diagnostic accuracy of circulating microRNA for the differentiation of adrenocortical adenoma and adrenocortical
cancer
MiRNA Type of sample Comparison Sensitivity Specificity AUC Reference

hsa-miR-34a S ACA-ACC ND ND 0.81 [22]

hsa-miR-483–5p ND ND 0.74
hsa-miR-195 S ACA-ACC 90.9 100 0.948 [23]
hsa-miR-139–5p 87.5 65 0.714
hsa-miR-335 95.2 71.4 0.837
hsa-miR-376a 71.4 85.7 0.811
hsa-miR-483–5p naACC-aACC 85.7 100 0.929
dCThsa-miR-210 -dCThsa-miR-181ba P ACA-ACC 88.9 75 0.87 [11]
a
dCThsa-miR-100/dCThsa-miR-181b 77.8 100 0.85
hsa-miR-483–5p P-EV ACA-ACC 87.5 94.44 0.965 [13 ]
&

hsa-miR-101 68.75 83.33 0.766

hsa-miR-320b P-EV CPA-CP-ACC 88.89 76.92 0.863 [27 ]
&

aACC, aggressive ACC; AUC, area under curve; CPA, cortisol-producing adenoma; CP-ACC, cortisol-producing ACC; CT, cycle threshold; EV, extracellular
vesicle; naACC, nonaggressive ACC; ND, no data; P, unfractionated plasma; S, unfractionated serum.
a
Combination of miRNA markers used.

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Adrenal cortex and medulla
shown the association of circulating hsa-miR-483–
5p to tumor stage and diameter, and its utility as a
marker of recurrence. Circulating miRNA can thus
be proposed as potential markers for ACC follow-up,
but studies on larger cohorts are warranted.
ADRENAL MYELOLIPOMA
We have recently studied the tissue miRNA expres-
sion profiles of AML and investigated the circulating
counterparts of tissue miRNAs showing significant
differences in expression. AML is the second most
common, invariably benign adrenal incidentaloma,
and it may sometimes cause differential diagnostic
problems in imaging because of the variability of fat
& &&
and bone marrow components [32 ]. Circulating
hsa-miR-451a and hsa-miR-363–3p were overex-
pressed in AML vs. benign and malignant adreno-
cortical tumors. By receiver operator characteristics
analysis, the area under curve values of hsa-miR-
451a were 0.876 and 0.909 vs. ACA and ACC, respec-
tively. Overexpressed hsa-miR-451a displayed a neg-
ative predictive value of 83.33% to rule out ACC,
whereas its positive predictive value to confirm AML
was 90%. Circulating hsa-miR-451a is thus a prom-
ising biomarker for AML, and its overexpression
might help in the differential diagnosis of rare cases
in which the imaging features are not unequivocal
for either AML or ACC. Another major finding in
this study is related to the lack of significant differ-
ence in expression of hsa-miR-483–5p both in tissue
and plasma between ACC and AML. This represents
a limitation in the clinical applicability of hsa-miR-
483–5p as a marker of adrenocortical malignancy
&
[24 ]. Moreover, even it is pure hypothesis at pres-
ent, the similar expression of hsa-miR-483–5p
between AML and ACC might even be related to
some common steps in their pathogenesis.
PHEOCHROMOCYTOMA
Despite some findings on the differential expression
of tissue miRNA in various types of PHEOs [33–36],
there are only a few studies on the expression of
circulating miRNA in PHEO/paraganglioma
patients. A marker for PHEO malignancy would be
desperately needed, as its malignant behavior can
only be confirmed by clinical observation. Based on
their differential expression in benign and malig-
nant PHEO tissues, Patterson et al. [35] investigated
the expression of hsa-miR-483–5p, hsa-miR-101, and
hsa-miR-183 in benign and malignant PHEO
patients’ sera but found no differences in expres-
sion. No significant difference of circulating hsa-
miR-101 was found in PHEO patients in a further
study, either [37]. It is interesting to note that some
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overexpressed tissue miRNAs (hsa-miR-483–5p and
hsa-miR-101) seem to be shared by malignant adre-
nocortical and adrenomedullary tumors despite
their different developmental origin.
POTENTIAL BIOLOGICAL RELEVANCE OF
CIRCULATING MICRORNA IN ADRENAL
TUMORS
The biological relevance of these miRNA can only
be hypothesized at present in adrenal tumors. The
overexpressed, extracellular vesicle-associated cir-
culating miRNA might enter other cells and thus
alter, for example, tumor microenvironment,
immune homeostasis, promote metastasis forma-
tion, so on [38 ]. Except for some tissue miRNA,
such as hsa-miR-210 that is overexpressed under
hypoxic conditions and in many tumors including
ACC [29], very little is known on the biological
activity of miRNA in adrenal tissues. A recent study
showed that hsa-miR-483–5p and miR-139–5p can
be implicated in ACC pathogenesis by targeting N-
myc downstream-regulated gene family members
&
[39 ]. The PUMA protein (p53 upregulated modula-
tor of apoptosis) was shown to be a potential target
of hsa-miR-483–3p [40] that was confirmed in ACC
[41], as well. The potential link of hsa-miR-483–3p
to the p53 pathway has been also shown in hepato-
cellular carcinoma [42]. These findings, however,
have only shed light on the potential biological
activity of some tissue miRNA in ACC, but the
biological activity of their circulating counterparts
is unclear, yet.
CONCLUSION
Circulating miRNAs represent a group of very inter-
esting small RNA molecules with a great potential as
biomarkers in tumor diagnosis belonging to liquid
biopsy. Several data underline their utility in the
differential diagnosis of adrenocortical tumors and
also in AML, however, there are no findings for
adrenomedullary tumors to date. Uniform require-
ments for the methodology on circulating miRNA
are required to diminish interassay variabilities and
to enhance their reliability in diagnosis. Despite
many data on their applicability in diagnosis, their
biological relevance is much less clarified.
Acknowledgements
None.
Financial support and sponsorship
The study has been supported by a grant from the
Hungarian National Research, Development and Inno-
vation Office (NKFIH K115398) to P.I. The presented
Volume 26  Number 3  June 2019

research activities were financed by the Higher Education
Institutional Excellence Programme of the Ministry of
Human Capacities in Hungary, within the framework of
the molecular biology thematic programme of the Sem-
melweis University.
Conflicts of interest
There are no conflicts of interest.
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