Role of components of microRNA machinery in carcinogenesis
MicroRNAs (miRNAs) are a broad class of non-coding RNAs nearly 21 nucleotides length, which play crucial functions in posttranscriptional gene regulation. These molecules are associated with many developmental and cellular processes in eukaryotic organisms. Current investigation has reported major f...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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| Цитувати: | Role of components of microRNA machinery in carcinogenesis / R. Kian, S. Moradi, S. Ghorbian // Experimental Oncology. — 2018 — Т. 40, № 1. — С. 2–9. — Бібліогр.: 97 назв. — англ. |
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Kian, R. Moradi, S. Ghorbian, S. 2018-06-19T21:13:51Z 2018-06-19T21:13:51Z 2018 Role of components of microRNA machinery in carcinogenesis / R. Kian, S. Moradi, S. Ghorbian // Experimental Oncology. — 2018 — Т. 40, № 1. — С. 2–9. — Бібліогр.: 97 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/139254 MicroRNAs (miRNAs) are a broad class of non-coding RNAs nearly 21 nucleotides length, which play crucial functions in posttranscriptional gene regulation. These molecules are associated with many developmental and cellular processes in eukaryotic organisms. Current investigation has reported major factors contributing to miRNA biogenesis and has constituted basic principles of miRNA function. More recently, it was confirmed that various miRNAs are clearly implicated in human malignancies, such as lung, breast, ovarian, bladder, colon cancer and other kinds of carcinoma. In addition, dysregulation in the miRNA machinery elements such as Dicer, Drosha, DGCR8, Argonaut, and TRBP could be involved in the progress of many tumor types. The purpose of the current review was to compile growing information besides how miRNA biogenesis and gene silencing are modified to develop cancer. en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Reviews Role of components of microRNA machinery in carcinogenesis Article published earlier |
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Role of components of microRNA machinery in carcinogenesis |
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Role of components of microRNA machinery in carcinogenesis Kian, R. Moradi, S. Ghorbian, S. Reviews |
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Role of components of microRNA machinery in carcinogenesis |
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Role of components of microRNA machinery in carcinogenesis |
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Role of components of microRNA machinery in carcinogenesis |
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Role of components of microRNA machinery in carcinogenesis |
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role of components of microrna machinery in carcinogenesis |
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Kian, R. Moradi, S. Ghorbian, S. |
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Kian, R. Moradi, S. Ghorbian, S. |
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Reviews |
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2018 |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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MicroRNAs (miRNAs) are a broad class of non-coding RNAs nearly 21 nucleotides length, which play crucial functions in posttranscriptional gene regulation. These molecules are associated with many developmental and cellular processes in eukaryotic organisms. Current investigation has reported major factors contributing to miRNA biogenesis and has constituted basic principles of miRNA function. More recently, it was confirmed that various miRNAs are clearly implicated in human malignancies, such as lung, breast, ovarian, bladder, colon cancer and other kinds of carcinoma. In addition, dysregulation in the miRNA machinery elements such as Dicer, Drosha, DGCR8, Argonaut, and TRBP could be involved in the progress of many tumor types. The purpose of the current review was to compile growing information besides how miRNA biogenesis and gene silencing are modified to develop cancer.
|
| issn |
1812-9269 |
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https://nasplib.isofts.kiev.ua/handle/123456789/139254 |
| citation_txt |
Role of components of microRNA machinery in carcinogenesis / R. Kian, S. Moradi, S. Ghorbian // Experimental Oncology. — 2018 — Т. 40, № 1. — С. 2–9. — Бібліогр.: 97 назв. — англ. |
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| first_indexed |
2025-11-27T03:14:06Z |
| last_indexed |
2025-11-27T03:14:06Z |
| _version_ |
1850796524101959680 |
| fulltext |
2 Experimental Oncology 40, 2–9, 2018 (March)
ROLE OF COMPONENTS OF microRNA MACHINERY
IN CARCINOGENESIS
R. Kian, S. Moradi, S. Ghorbian*
Department of Molecular Genetics, Ahar Branch, Islamic Azad University, Ahar 54511, Iran
MicroRNAs (miRNAs) are a broad class of non-coding RNAs nearly 21 nucleotides length, which play crucial functions in post-
transcriptional gene regulation. These molecules are associated with many developmental and cellular processes in eukaryotic
organisms. Current investigation has reported major factors contributing to miRNA biogenesis and has constituted basic principles
of miRNA function. More recently, it was confirmed that various miRNAs are clearly implicated in human malignancies, such as lung,
breast, ovarian, bladder, colon cancer and other kinds of carcinoma. In addition, dysregulation in the miRNA machinery elements
such as Dicer, Drosha, DGCR8, Argonaut, and TRBP could be involved in the progress of many tumor types. The purpose of the
current review was to compile growing information besides how miRNA biogenesis and gene silencing are modified to develop cancer.
Key Words: DGCR8, miRNA machinery components, miR, cancer, regulator.
Several types of short non-coding RNAs including
small interfering RNAs (siRNAs), Piwi-interacting RNAs
(piRNAs) and microRNAs (miRNAs) have a principal
and crucial regulatory functions of development pro-
cesses in all eukaryotes [1]. Formerly, a finding re-
vealed the first miRNAs in Caenorhabditis elegans [2].
miRNAs are extremely protected from species and
supposedly may regulate up to 30% of all genes in the
human genome [3, 4]. miRNAs are small noncoding
RNAs of 18–24 nt in length that controls gene expres-
sion post-transcriptionally [5] via negative regulation
through binding to the 3'-untranslated region (3'-UTR)
of mRNA transcripts, stimulating translational suppres-
sion or break of the target [6, 7]. Multiple thousands
of miRNAs have been classified in humans and they are
evolutionarily conserved. Lately, it has been uncovered
that variable expression of special miRNA genes could
be increased during the beginning and improvement
of cancer [8]. Accordingly, cancer-associated al-
terations in miRNA expression models are emerging
as promising diagnostic markers often compared
with disease improvement and survival rates, thus
offering a new window for treatment of another can-
cer types [9]. In general, miRNAs can control several
processes, including metabolism, cell differentiation,
proliferation and survival, inflammation, genome sta-
bility, tumor invasion and angiogenesis [10]. Appearing
in the cell nucleus, miRNA operation on the regula-
tion of gene expression continues in the cytoplasm
by binding to its supplementary base-sequence of the
targeted mRNA molecule. Subsequently, gene silenc-
ing through degradation of target mRNA or inhibition
with the translation process takes its place [11]. Pres-
ently hundreds of miRNAs have been distinguished
in different species [12]. Notwithstanding, most
miRNA research is focused on the growth and progress
of stem cells, differentiation, tumorigenesis and other
pathological processes [13].
miRNA BIOGENESIS AND MECHANISM
OF ACTION
Mainly, miRNAs are encoded within the genome
and are transcribed by RNA polymerase II (Pol II)
or RNA polymerase III (Pol III) as long precursor
transcripts, known as primary miRNAs (pri-miRNAs)
of several kilobases (kb) in length [14]. Mature miRNAs
are produced from pri-miRNAs by sequential process-
ing strategies. Conventionally animal pri-miRNAs pos-
sess nearly 33 bp stem and have a terminal loop struc-
ture with flanking segments [15]. Precursor miRNAs
(pre-miRNAs) are commonly the microprocessor
system in the nucleus, whose core components are
the RNase III enzyme Drosha and its binding partner
DiGeorge syndrome critical region 8 (DGCR8) [16].
Approximately 31% of miRNAs are prepared from
introns of protein-coding genes, whereas many other
miRNAs are expressed from committing miRNA gene
loci. An own pri-miRNA can either produce a single
miRNA or contain clusters of two or more miRNAs that
are changed from a regular primary transcript [17].
However, these long pri-miRNAs are cleaved by Micro-
processor, comprising the double-stranded RNase III
enzyme Drosha and its crucial cofactor, the double-
stranded RNA binding protein DGCR8 [18]. In this
pathway, the nuclear splicing machinery supplies
pre-miRNA from introns. miRNAs originated from this
process are appropriately termed mirtrons. These
molecules enclose a short class of miRNAs, but are
identified in multiple organisms [19]. Preliminary, the
nuclear microprocessor complex identifies the miRNA
hairpins in the main transcript and cleaves each hair-
pin roughly 11 nucleotides from its base [20]. Recent
manifestation suggests that some miRNAs that survive
Submitted: November 21, 2016.
*Correspondence: E-mail: ghorbian20@yahoo.com
Abbreviations used: 3'-UTR — 3'-untranslated region; BC — breast can-
cer; BCC — basal cell carcinoma; DGCR8 — DiGeorge syndrome critical
region 8; HCC – hepatocellular carcinoma; miRNAs — microRNAs;
PACT — PKR activating protein; P-bodies — processing bodies;
PCMM – primary cutaneous malignant melanoma; piRNAs – Piwi-inter-
acting RNAs; pre-miRNAs – precursor miRNAs; pri-miRNAs – primary
miRNAs; RISC — RNA-induced silencing complex; SCC – squamous
cell carcinoma; siRNAs – small interfering RNAs; TRBP – transactiva-
tion-responsive RNA-binding protein; XPO5 — exportin-5.
Exp Oncol 2018
40, 1, 2–9
REVIEWS
Experimental Oncology 40, 2–9, 2018 (March)40, 2–9, 2018 (March) (March) 3
within introns, the so-called mirtrons, bypass Drosha
break and depend on the proceeding of the pre-mRNA
splicing machinery to originate an approximately
60 nt pre-miRNA hairpin [21]. Regardless of whether
the pre-miRNA hairpin is excised from the initial
transcript by canonical Drosha break or through the
mirtron pathway, the next stage in the miRNA biogen-
esis is recognition of the nearly 60 nt pre-miRNA by ex-
portin-5 (XPO5) and export to the cytoplasm in a ran
guanine triphosphatase-dependent manner [22].
Mirtrons encompass a small cluster of miRNAs, but
are found in numerous organisms. Pre-miRNAs are
transported from the nucleus to the cytoplasm by the
exportin-5/RanGTPheterocomplex [23]. Complex
in cytoplasm compromised of Dicer RNase III endo-
nuclease, transactivation-responsive RNA-binding
protein (TRBP), and protein kinase Re-activating.
Protein further cleaves the pre-miRNA generating
a short double-stranded miRNA:miRNA complex
intermediate [24]. In the cytoplasm, pre-miRNAs are
processed by RNase III enzyme Dicer. Dicer is thought
to react with dsRBDs-containing partner proteins, HIV
TRBP and/or PKR activating protein (PACT) [25]. Then,
Dicer cleaves pre-miRNAs into 21–25 nt long miRNA/
miRNA duplexes, each strand of which bears 5' mono-
phosphate, 3' hydroxyl group and a 3' 2-nt overhang.
It preferentially incorporates one of the duplex strands
into the RNA-induced silencing complex (RISC).
Of a miRNA/miRNA duplex, only one strand, designat-
ed the miRNA strand, is selected as the guide of mature
RISC, whereas the other strand, the miRNA strand,
is discarded during RISC assembly [26]. Such biased
strand selection depends on the stability of at least
three properties of a miRNA/miRNA duplex: the struc-
ture; the 5' nucleotide identity; and the thermodynamic
asymmetry [27]. These findings propose miRNA pro-
cessing by Dicer, during RISC loading, and target RNA
cleavage by argonaute 2 (Ago2) is coupled [28]. The
translational repression mechanism by miRNAs has
been poorly understood. Recently, it was declared
that the target mRNAs binding to RISC through partial
base pairing, are accumulated in the cytoplasmic foci
referred to as processing bodies (P-bodies). P-bodies,
in which the mRNAs are stored or degraded by the
decapping enzymes and exonucleases, do not contain
the translational machinery [29] (Figure).
DICER
Dicer, a critical RNase III endonuclease of the
miRNA processing, performs a role in carcinogenesis
and various types of human malignancies [30]. Dicer
is a large multi-domain protein with a principal func-
tion for the last step of miRNA and short-interfering
RNA biogenesis. In human and mouse cell lines,
Dicer is considered to act in the nuclear clearance
of dsRNA as well as the foundation of chromatin agree-
ments [31]. Dicer is supposed to play an essential
function in the biogenesis of eukaryotic small RNAs/
miRNAs; Dicer target transcripts have not been directly
mapped. Interestingly, mainly Dicer-binding sites
remain on mRNAs/lncRNAs and are not substantially
prepared into miniature RNAs. These passive sites
normally harbor short, Dicer-bound hairpins with
entire transcripts and regularly maintain target ex-
pression [32]. Dicer, single of the proteins implicated
in the synthesis miRNA, is implicated in the biogenesis
of miRNAs and is influential in carcinogenesis and
cancer progress and progression [33]. Low expression
of Dicer gene and protein linked to poor prognosis and
recurrence of cervical cancer.
In addition, the investigation revealed that de-
creased Dicer gene expression and protein levels are
associated with metastasis relapse and tumor stage.
The patients with decreased Dicer miRNA and protein
expression displayed a shorter 5-year disease-free
survival and overall survival. Moreover, low expression
of Dicer befits to be a significant prognostic factor
for cervical malignancy and other tumor types [34].
Previous studies have shown that inhibition of Dicer
in von Hippel — Lindau deficient clear cell renal cell
carcinoma contributed to the high levels of the hy-
poxia-inducible factors-2α and a cancer phenotype,
which suggests Dicer could be a useful therapeutic
target for managing this disease [35]. miR-200a and
miR-31 are targeted for Dicer and are involved in the
carcinogenesis, cell migration, and behavior of castra-
tion-resistant prostate cancer, showing that they could
be possible biomarkers for monitoring of prostate
cancer progression [36]. The Dicer protein expres-
sion is significantly associated with hormone recep-
tor status and cancer subtype in breast tumors [37].
Drosha and Dicer1 mutations impair expression
of tumor-suppressing miRNAs, including the let-7 fam-
ily, significant regulators of MYCN, LIN28 and other
Wilms tumor oncogenes. Current findings explored the
mechanisms through which mutations in miRNA bio-
genesis components reprogrammed miRNA expres-
Figure. Schematic presentation of the miRNA biogenesis and
functional mechanisms. The miRNA genes are transcribed
by RNA polymerase II (Pol II) as long precursor transcripts
(pri-miRNAs). These long pri-miRNAs are cleaved by RNase III
enzyme Drosha and DGCR8. Pre-miRNAs are exported from the
nucleus to the cytoplasm by the XPO5/RanGTP heterocomplex.
Complex in cytoplasm compromised of Dicer RNase III endo-
nuclease and TRBP. Protein further cleaves the pre-miRNA
generating a short double-stranded miRNA:miRNA complex
intermediate. miRNA/miRNA duplex, only one strand,designated
the miRNA strand, is selected as the guide of mature RISC and
target RNA cleavage by AGO2 is coupled
4 Experimental Oncology 40, 2–9, 2018 (March)
sion in human malignancies and proposed that these
defects clarify a distinct subclass of Wilms tumors [38].
However, several investigations have revealed that
dysregulation of Dicer gene are observed in many
disorders, including upregulation in Dicer1 gene ex-
pression with tumor stages and progression of prostate
cancer and smooth muscle tumors [39]. In addition,
preliminary investigations revealed that upregulation
of Dicer1 is correlated with gastric tumor subtype and
advanced tumor stages in gastric cancer and serous
ovarian cancer [40, 41]. However, the other studies
showed that the increased Dicer1 expression levels
are required for proliferation of oral cancer cells [42].
Faber et al. [43] evaluated Dicer1 expression levels
in colorectal cancer, and revealed an increased level,
which is associated with tumor stage and poor survival
of the patients. Chiosea et al. [44] disclosed that up-
regulation of Dicer1 expression levels are associated
with histological subtypes and stages of lung cancer.
Ma et al. [45] showed that up-regulated Dicer1 expres-
sion levels correlated with clinical stage of cutaneous
melanoma. In general, Dicer expression levels are
different in various cancer types; Witkowski et al. [46]
revealed that downregulation of Dicer1 expression
levels is associated with the altered miRNA profile
in patients with bladder cancer. Pampalakis et al. [47]
revealed that decreased Dicer1 expression levels
are associated with advanced tumor stage and poor
survival of ovarian cancer patients. Contradictory
to the other findings, Torres et al. [48] showed that
downregulation of Dicer1 gene is not associated with
histological grade in patients with endometrial cancer.
Guo et al. [49] observed the decreased expression
of Dicer1, which correlated with lower survival of pa-
tients with nasopharyngeal carcinoma. In addition, Lin
et al. [50] revealed that Dicer1 expression levels were
significantly lower and associated with total downregu-
lation of miRNAs and poor outcome of patients with
neuroblastoma. Khoshnaw et al. [51] revealed that
decreased Dicer1 expression levels are associated
with breast cancer (BC) progression and recurrence.
Furthermore, investigations displayed that decrease
of Dicer1 levels are correlated with metastasis, in-
vasion and poor prognosis and shortened survival
in the patients with gallbladder adenocarcinoma and
non-small cell lung cancer [52, 53]. Wu et al. [54]
revealed that downregulation of Dicer1 is not asso-
ciated with clinical characteristics of hepatocellular
carcinoma (HCC). Findings in other studies revealed
that decreased Dicer1 expression levels are associ-
ated with progression, tumor stage, prognosis and
shorter survival of patients with chronic lymphocytic
leukemia, colorectal cancer, BC, and papillary thyroid
carcinoma (Table) [55–59].
DROSHA
Drosha involves two RNase III domains, which
performs a vital role in miRNA biogenesis; Drosha
and its double-stranded RNA-binding partner protein
Pasha/DGCR8 likely identify and cut miRNA precursor
RNAs or pri-miRNA hairpins co-transcriptionally [60].
Long pri-miRNAs are cleaved by microprocessor
complex comprising of Drosha, a type III ribonucle-
ase (RNase III), and an RNA-binding protein DGCR8,
is so called because a Drosha/DGCR8 complex
is essential and sufficient to process a pri-miRNA
into a pre-miRNA hairpin in vitro. Dicer then cleaves
the pre-miRNA hairpin at the loop to form the mature
miRNA. Correct Drosha cleavage in the pri-miRNA
is critical to the production of a functional miRNA [61].
Drosha is an important factor for miRNA biogenesis
and as such obligatory for cellular homeostasis and
developmental processes. Together with its cofactor
DGCR8, it changes the pri-miRNA into the pre-miRNA
in the nucleus. Whilst the middle and the C-terminal
domain are important for pri-miRNA processing and
DGCR8 binding, the activity of the N-terminus remains
mysterious. Different investigations have linked this
region to the subcellular localization of Drosha, stabi-
lization, and response to tension [62]. The repression
occurs solely in mature miRNAs and not in pri-miRNA
transcripts, evidencing that the Drosha E1147K muta-
tion affects processing of pri-miRNAs. The pivotal role
of the miRNA biogenesis pathway is shown in Wilms
tumor development, particularly the major miRNA
processing gene Drosha [63]. Decreased expres-
sion of Drosha was found in melanoma. Furthermore,
the irregular subcellular location of Drosha reveals
potential deregulation in the procedures responsible
for its proper localization in the nucleus [64]. The new
results show that cytoplasmic Drosha potentially plays
a role in blocking carcinogenesis and progression
of gastric cancer and may serve as an independent
prognostic marker [65]. The copy number discrepancy
of Dicer1 and Drosha correlates well with their expres-
sion levels and survival of patients with non-small cell
lung cancer and other cancer types. The increased
expression of Drosha and Dicer1 are associated
with decreased and increased survival, respectively.
As a result, copy number variation may be a sig-
nificant mechanism of upregulation/downregulation
of miRNAs in malignancy and propose an oncogenic
role for Drosha [66]. Muralidhar et al. [39] revealed that
upregulation of Drosha expression levels could alter
miRNA profile associated with neoplastic progression
in cervical squamous cell carcinoma (SCC). In ad-
dition, Sugito et al. [67] have shown that increased
Drosha expression was associated with poor sur-
vival of patients with esophageal cancer. The findings
of several investigations have shown that upregulation
of Drosha was associated with tumor progression,
advanced tumor stages and poor prognosis in the pa-
tients with various cancer types [37–39, 51]. Moreover,
Sand et al. [68] revealed that upregulation of Drosha
expression levels was not determined in SCC and
basal cell carcinoma (BCC). Avery-Kiejda et al. [69]
revealed that upregulation of Drosha expression levels
had no significant clinical correlation in triple-negative
BC. Similarly, in others investigations, findings showed
that downregulation of Drosha expression levels could
Experimental Oncology 40, 2–9, 2018 (March)40, 2–9, 2018 (March) (March) 5
alter miRNA profile and correlated with poor patient
survival, histological grade, metastasis, invasion and
poor prognosis in many cancer types [48–50, 52, 64,
70, 71]. Findings revealed that altered Drosha expres-
sion levels are not associated with clinical features
in colorectal cancer, BC, and papillary thyroid carci-
noma (see Table) [57–59].
DGCR8
Mirtrons pathways include a small class of miRNAs;
although miRNAs are synthesized via the miRtron
pathway rather than by Drosha, the synthesis of main
miRNAs looks to be Drosha dependent. The prominent
stem-loop in pri-miRNAs is identified through Dro-
sha together with its partner Pasha/DGCR8. Indeed,
Pasha/DGCR8 is thought to bind preferentially at the
junction between the stem and the more inflexible
loop, and this process can be co-transcriptional.
This binding then positions Drosha midway up to the
stem so that it is correctly positioned to make a pair
of staggered breaks to generate the nearly 70 bp pre-
miRNA [72]. The microprocessor complex mediates
intranuclear biogenesis of pre-miRNAs from the pri-
miRNA transcript. Extranuclear, mature miRNAs are
merged into the RISC before interaction with complet-
ing target mRNA that leads to repression of translation
Table. Patterns of miRNA expression in different tumor types
Genes Increase or decrease Cancer type Refs
Drosha Altered miRNA profile; associated with neoplastic progression Cervical SCC [39]
Regulates cell proliferation; associated with poor patient survival Oesophageal cancer [67]
Associated with pathological characteristics and patient survival Gastric cancer [40]
Associated with advanced tumor stages Serous ovarian carcinoma [41]
Associated with poor prognosis Non-small cell lung cancer [53]
Not determined SCC and BCC [68]
No clinical correlation Triple-negative BC [69]
Altered miRNA profile Bladder cancer [70]
Associated with poor patient survival Ovarian cancer [71]
Correlated with histological grade Endometrial cancer [48]
Correlated with shorter patient survival Nasopharyngeal carcinoma [49]
Correlated with metastasis, invasion and poor prognosis Gallbladder adenocarcinoma [50]
Correlated with total downregulation of miRNAs and poor outcome Neuroblastoma [52]
Associated with cancer progression and poor survival Cutaneous melanoma [64]
Down-regulated BC [58]
Significantly upregulated, not associated with clinical characteristics Colorectal cancer [57]
Significantly lower expressed, not associated with clinical characteristics Papillary thyroid carcinoma [59]
Dicer Correlated with a gastric tumor subtype
Gastric cancer [40]
Associated with advanced tumor stages Serous ovarian carcinoma [41]
Required for proliferation Oral cancer [42]
Correlated with tumor stage and associated with poor survival Colorectal cancer [43]
Associated with histological subtypes and stages Precursor lesions of lung adenocarcinoma [44]
Correlated with clinical stage Cutaneous melanoma [45]
Altered miRNA profile Bladder cancer [46]
Associated with advanced tumor stage and poor patient survival Ovarian cancer [47]
No association with histological grade detected Endometrial cancer [48]
Correlated with shorter patient survival Nasopharyngeal carcinoma [49]
Associated with a total down regulation of miRNAs and poor outcome Neuroblastoma [50]
Associated with cancer progression and recurrence BC [51]
Correlated with metastasis, invasion and poor prognosis Gallbladder adenocarcinoma [52]
Low levels of DICER1 expression correlate with shortened survival Non-small cell lung cancer [53]
Not associated with clinical characteristics HCC [54]
Associated with progression and prognosis Chronic lymphocytic leukemia [55]
Associated with tumor stage and shorter survival Colorectal cancer [56]
Significantly upregulated, not associated with clinical characteristics Colorectal cancer [57]
Significantly altered gene expression, not associated with clinical char-
acteristics
Papillary thyroid carcinoma [59]
Down-regulated BC [58]
DGCR8 Associated with poor patient survival Oesophageal cancer [67]
Altered miRNA profile Bladder cancer [70]
Not determined SCC and BCC [68]
Associated with dysregulated miRNA Prostate cancer [64]
Not associated with any clinical parameters Colorectal carcinoma [73]
Required for cell proliferation, migration and invasion Ovarian cancer [75]
Significantly altered gene expression, not associated with clinical char-
acteristics
Papillary thyroid carcinoma [59]
XPO5 Associated with an altered miRNA profile Bladder cancer [70]
AGO1/AGO2 Not determined Actinic keratoses, SCC and BCC [68]
Associated with advanced tumor stages Serous ovarian carcinoma [41]
Correlated with advanced tumor stages and associated with shorter sur-
vival
Significantly lower expressed, not associated with clinical characteristics Papillary thyroid carcinoma [59]
TRBP Amplified in BC BC [85]
Significantly up-regulated, associated with clinical characteristics BC [87]
Significantly up-regulated Malignant melanoma [88]
Significantly up-regulated Diffuse large B cell lymphomas [96]
Significantly up-regulated, not associated with histopathological and
clinical parameters
Adrenocortical carcinoma [97]
Altered miRNA profile Ewing sarcoma [98]
Notes: AGO — Argonaute; BC — breast cancer; BCC — basal cell carcinoma; DGCR8 — DiGeorge syndrome critical region 8; SCC — squamous cell carcino-
ma; XPO5 — exportin-5; TRBP — transactivation-responsive RNA-binding protein.
6 Experimental Oncology 40, 2–9, 2018 (March)
or mRNA destabilization. The DGCR8 is a component
of microprocessor complex crucial for miRNA matura-
tion. The Ago2 proteins are a component of a complex
protein named as RISC. A previous investigation has
shown that DGCR8 mRNA expression is down-regu-
lated in prostate cancer. Upregulated DGCR8 mRNA
expression has been found in epithelial skin cancer and
pleomorphic adenomas of the salivary gland. It has
been documented that the Ago2 mRNA expression
level is up-regulated in epithelial skin cancer [73].
Firstly, the DGCR8 mRNA expression level was up-reg-
ulated in colorectal cancer, evidencing on its role in the
pathobiology of the colorectal carcinogenesis [74].
DGCR8 was expressed in ovarian cancer. MiR-27b
was detected as significantly down-regulated miRNA
in DGCR8-knockdown cells and endorsed cell prolif-
eration in ovarian cancer cells [75]. Preliminary stud-
ies reported that expression levels of Drosha in AGS
and HepG2 cell lines were higher than in the controls,
whereas, Drosha expression level in KYSE-30 cell line
was lower. The Dicer expression levels in AGS and
HepG2 cells were increased, whereas, its expression
level in KYSE-30 cell was lower. The DGCR8 expression
levels in all three cell lines were significantly higher
than in the control samples [76]. In addition, Sugito
et al. [67] revealed that upregulation of DGCR8 ex-
pression was associated with poor survival of patients
with esophageal cancer. Catto et al. [70] showed that
increased DGCR8 expression levels altered the miRNA
profile in bladder cancer. Sand et al. [68] reported that
upregulation of DGCR8 expression was not determined
in SCC and bladder cancer, additionally, revealed that
up-regulated DGCR8 expression was associated with
dysregulated miRNA in prostate cancer. Kim et al. [73]
revealed that upregulation of DGCR8 expression was
not associated with any clinical parameters in colorec-
tal carcinoma. Furthermore, Guo et al. [49] revealed
that increased DGCR8 expression levels were required
for cell proliferation, migration, and invasion in ovarian
cancer. Findings revealed that altered DGCR8 expres-
sion is not associated with clinical features in papillary
thyroid carcinoma [59].
AGO
Pre-miRNAs exported into the cytoplasm are pro-
cessed by another RNase III enzyme, Dicer, into nearly
21 bp double-stranded miRNA-miRNA duplexes and
moved into the groove of AGO. Afterwards the miRNA
strand dissociation, mature single-stranded miRNA
remains loaded into and stabilized by AGO1. AGO was
subsequently separated from Dicer to bind TNRC64,
an essential co-factor in the miRNA-induced silenc-
ing complex [77]. AGO2 is a major part of the RISC
that can directly deteriorate mRNA through slicing
AGO2 amasses in cytoplasmic processing bodies,
where additional binding interactions promote transla-
tional inhibition and mRNA decay. AGO2 also couples
with MVEs in structures that have been called “GW-
bodies” because of the presence of GW182 but lack
of other P-body components. Current reports have
demonstrated that AGO2 binds to miRNAs to generate
AGO2-miRNA complexes that are found in the extra-
cellular space. Although the majority of descriptions
illustrates Ago2 as being present in the extracellular
space as a free protein, other investigations have
shown that AGO2 and other RNA-processing pro-
teins are present in the secreted exosomes [78]. The
genetic polymorphism of AGO2 may be a risk factor
for the progressive lymph node metastasis in naso-
pharyngeal carcinoma in the Chinese population,
and AGO2 acts as an oncogene in the development
of nasopharyngeal carcinoma [79]. Sand et al. [68]
revealed that upregulation of AGO1 and AGO2 expres-
sion was not determined in actinic keratosis, SCC and
BCC, while such upregulation was associated with
advanced tumor stages in serous ovarian carcinoma.
Findings revealed that the AGO2 expression levels
was significantly lower in neoplastic tissues compared
to the healthy tissues in papillary thyroid carcinoma
(see Table) [59].
XPO5
XPO5 is a component of the importin-β family
of proteins that consist of one major class of nucleo-
cytoplasmic transporters. XPO5 binds directly to its
pre-miRNA cargo in a Ran-GTP-dependent manner.
As well, XPO5 is capable of recognizing and export
structured RNAs that are unrelated to pre-miRNAs,
involving viral mini-helix RNA and tRNA, along with
certain other proteins, such as STAU2, ILF3, and
JAZ. It has also been indicated that XPO5 is impor-
tant in siRNA biogenesis and therefore, is a basic
point of intersection between the siRNA and miRNA
pathways [80]. XPO5 is a transporter protein regularly
mediating pre-miRNAs nuclear export. Recent investi-
gations have displayed that XPO5 may play an impor-
tant role in some cancers. Anyway, little is known about
XPO5 in HCC [81]. The XPO5 genetic defect traps
pre-miRNAs in the nucleus decreases miRNA pro-
cessing and diminishes miRNA-target inhibition [82].
XPO5 knockdown promoted HCC cell migration and
decreased the expression of E-cadherin and p53.
Furthermore, after treatment with DAC and TSA, the
mRNA level of XPO5 was up-regulated in HCC cells,
implicating that epigenetic modulation may be involved
in the transcription of XPO5. Generally, these findings
suggest that XPO5 functions as a potential tumor sup-
pressor in the development and progression of HCC
as well as a promising molecular target for HCC ther-
apy [83]. Catto et al. [70] revealed that upregulation
of XPO5 expression was associated with the altered
miRNA profile in bladder cancer (see Table).
TRBP
miRNAs are transported from the nucleus to the
cytoplasm via XPO5 mediated pathway, where they
are bound with Dicer and the TRBP, and maturate into
double-stranded miRNAs. The active strand of such
mature miRNA is retained in the Dicer-TRBP com-
plex, which then binds with the endonuclease AGO2.
One strand of the mature miRNA (the guide strand)
Experimental Oncology 40, 2–9, 2018 (March)40, 2–9, 2018 (March) (March) 7
is loaded into the RISC target mRNAs that are comple-
mentary to the miRNA [84]. Huang et al. [85] revealed
that TRBP is overexpressed in BC. TRBP is multi-
functional and mediates crosstalk between different
pathways. The protein AIB3, also known as ASC-2,
RAP250, PRIP, TRBP, and NCR, is a newly recognized
nuclear receptor co-activator that is amplified and
over-expressed in BC [86]. Lin et al. [87] revealed
that the BC patients with cytoplasmic overexpression
of TRBP2 had shorter disease free survival and over-
all survival. Sand et al. [88] showed that TRBP2 was
significantly up-regulated in benign melanocytic nevi
compared to primary cutaneous malignant melanoma
(see Table). Earlier, we have applied a gold standard
method for lymphoma diagnosis using TRBP2 gene
expression analysis [89–95]. However, Caramuta
et al. [96] revealed that the expression of TRBP2 was
significantly higher in diffuse large B cell lymphomas
than in lymph nodes, and also in the adrenocortical
carcinomas compared with adenomas or normal ad-
renal cortices. Whereas, TRBP2 expression was not
correlated with histopathological and clinical param-
eters [97]. De Vito et al. [98] revealed that deregulation
of TRBP2 in the Ewing sarcoma.
In conclusion, the newest findings on miRNA ex-
pression patterns in cancerous tissues will allow to de-
velop the use of these molecules as novel biomarkers
for tumor diagnosis, prognosis, and therapy.
CONFLICT OF INTERESTS
The authors have declared no conflict of interests.
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