Review Article
The Effect of mi-RNAs in the Progress or Inhibition of Gastrointestinal Stromal Tumors
Shima Ardehkhani1, Seyed Mohammad Amin Kormi2,3* and Amir Azizi4
1Department of Biology, Payame Noor University, Iran
2Cancer Genetics Research Unit, Reza Radiation Oncology Center, Iran
3Department of Biology, University of Zabol, Iran
4Department of Biology, Islamic Azad University Tonekabon, Iran
*Corresponding author: Seyed Mohammad Amin Kormi, Department of Biology, Faculty of Science, University of Zabol, Islamic Republic of Iran
Published: 19 Apr 2018
Cite this article as: Ardehkhani S, Kormi SMA, Azizi A. The
Effect of mi-RNAs in the Progress or
Inhibition of Gastrointestinal Stromal
Tumors. Clin Oncol. 2018; 3: 1445.
Abstract
Gastrointestinal Stromal Tumor is considered as one of the rare tumors in the gastrointestinal tract
and is mainly found in the gastrointestinal lining and the interstitial cells of Cajal, more than half
of which arise in the stomach and the rest do in the small intestine and along the gastrointestinal
tract. Nowadays, the major role of micro-RNAs is known for any researcher. Our studies show
that micro-RNAs, which play an interfering role in the molecular processes, can have significant
destructive or very efficient and beneficial impact on all the stages from inception to final treatment.
This overview article deals with the various micro-RNAs impacting on this tumor from different
aspects and finally offers the best mi-RNA in terms of its properties.
Introduction
Gastrointestinal Stromal Tumors (GISTs) are like an abscess in the stomach lining [1], that
represent about 1% of total cancer cases and are clinically considered as the sub epithelial lesions.
While, its common areas for incidence are stomach and a small part of the intestine, but this
tumor may be developed and expanded in any part of the gastrointestinal tract [2]. The incidence
abundance of these mesenchyme tumors is 10 to 15 new cases per million people in a year. Most of
these tumors are developed by the activating mutations in the KIT genes which cause 80% - 85%
and in the PDGFRA genes which cause 5% - 7% of the tumor cases [3]. The receptor tyrosine kinase
type 3 (RTK), (CD117), and myeloid of the variable marker [4] or neuronal features are expressed
by 95% of the GISTs. A major part of the GISTs represent the activating mutations in the KIT gene
or in the receptors associating with the platelets derived from the growth factor receptor of alpha
(PDGFRA) and the mutations available in these two genes are mutually exclusive [5].
In terms of incidence area, these tumor types are more common in the stomach (about 60%)
and, as mentioned previously, they may also appear in the small intestine as the second area (about
30%). The other parts of the digestive tract are less likely to involve in this disease. Only 5% of the
GISTs have been found in the colon and less than 5% in the esophagus. In some cases, the primary
site of the stromal tumor is on the outside of the gastrointestinal tract and behind the peritoneum
which is described for less than 10% of the diagnosed cases [6].
A small proportion of the GISTs have been observed at the areas outside of the gastrointestinal
tract, like Mesentery, Peritoneum, and especially, Omentum [7]. On the other hand, the micro-RNAs
play an important role in tumorigenesis and it is observed that the abnormalities in the adjustment
of micro RNAs (mi-RNAs) are related to many of the diseases such as cancer [8,9]. Micro RNAs are
the small and single-stranded non-coding RNAs (approximately 20-22 nucleotides) which adjust
the target gene expression through binding to the complementary areas (seed sequences) in the
target gene’s mi-RNA [10]. About 30% of the human genes’ expression is estimated to be adjusted
by mi-RNAs. The mi-RNA synthesis is done by Drosha and Dicer key enzymes, which is basically
dependent on the mi-RNA/m-RNA interaction and causing RNA or RISC induced silencing complex
[11]. Normally, mi-RNAs are transcribed by RNA polymerase II; the same enzyme synthesizing the
cellular mRNAs’ transcription. The primary mi-RNA, similar to the cellular mRNAs, has a warhead
at the end of 5-prime and a polyadenylate tail at the end of 3-prime [12]. In addition, by the RNase
III and Drosha enzyme complexes that are attached to its adjustment subunit, they can be converted
into the primary mi-RNAs [13].
The mi-RNAs synthesis steps are continued through the activity
of the trimming enzymes on the leading double-stranded mi-RNAs.
These reactions occur in the core through the activities of an enzyme
called Drosha and in the cytosol by the activity of the enzyme Dicer1.
Mi-RNAs play an accurate role in the changes in gene expression, as
a dimer [14]. Mi-RNAs play also a highly accurate role in the genes’
switching and expression, as the adjustor bio-molecules [15].
Currently, there is a variety of drugs being used for the GIST
treatment, including Sorafenib, Imatinib, Sunitinib, and Nilotinib
[16].
The progressed GISTs (non-resectable and/or metastatic) are
resistant to conventional chemotherapy [17], but instead, sensitive
to the Tyrosine Kinase Inhibitors (TKIs), Imatinib, and Sunitinib.
Currently, 400 mg/day of Imatinib is used for the worldwide standard
first-level treatment of the progressed GISTs [18].
The Imatinib drug is used for treatment when the KIT/PDGFRA
mutations are specifically detected. In addition, there are many
different strategies that can be applied for recovery, such as increasing
the dosage of Imatinib from 400 mg to 800 mg per day, surgically
removal of the progressive lesion’s focus area, and the treatment
by Sunitinib malate and Regorafenib (both are the multi-purpose
tyrosine kinase inhibitors having anti-angiogenesis properties) which
are the drugs recorded for the second and third level, respectively
[19].
Figure 1
Discussion
Nowadays, the importance of mi-RNAs in tumor progression or
suppression is an obvious thing for the people. As mentioned earlier,
there are various mi-RNAs involved in gastrointestinal stromal tumor
and the list is increasingly being grown every day, the most important
among which are as follows:
Mi-RNA-21
Mi-RNA-21 has been reported as a negative regulator of the
tumor suppressors by targeting Bcl-2; and so, it may operate as a
potent inhibitor of the tumor as well as the induction of apoptosis
[22] in the GIST cells. In addition, the development of mi-RNA-21
can cause an increased sensitivity to Imatinib in the GIST cells which
represents a potential role in the GIST treatment [23].
In accordance with the various studies carried out, the mRNA
level associating with Bcl-2 was significantly up-regulated in the GIST
samples [22].
The observations indicated that the Bcl-2 gene mi-RNA-21 levels
(with β-act in as an internal reference gene) increased in the GIST
cells. This gene that encodes the pri-mi-R-21 (the primary transcript
consisting of mi-RNA21) is placed within the TMEM49 gene
intron area. Despite the overlapping of pri-mi-R-21 and TMEM49
in the same transcription direction, pri-mi-R-21 is independently
transcribed by its own promoter regions and ends in its own poly (A)
tail. After transcription, pri-mi-R-21 is finally processed to become
mature mi-R-21. The mi-R-21 was exposed to over-expression in
almost all cancer types and thus, was classified as an Onco-miR.
Despite the fact that pri-mi-R-21 has a promotional area for its own,
but it has been found that mi-R-21 is subjected to up-regulation
in many pathological conditions such as cancer. There has been
proposed a non-transcriptional mechanism for up-regulating the
mi-R-21 gene proliferation instead of over-activating the promoter.
However, many of the available data indicate that the regulation of
the mi-R-21 expression continues in the transcription process and
the post-transcription level. The pri-mi-R-21 potent promoter areas
have been fully investigated but, there is still much discussion about
the actual size of pri-mi-R-21, the Transcription Start Site (TSS), and
the minimal promoter of pri-mi-R-21 [24].
Mi-RNA-518a-5p
Mi-RNA-518a-5p decreases the proliferation rate and increases
apoptosis in 822R. The low expression of mi-RNA-518a-5p is likely
to increase the PIK3C2A expression and affect the cellular response
to the drugs. PIK3C2A is a specific gene target for mi-RNA-518a-5p
in the GISTs resistant to Imatinib mesylate. The micro-error analyses
showed that mi-RNA-518a-5p found in the cells of the GISTs resistant
to Imatinib were subjected to a decrease in the expression and such
a decrease in the expression of mi-RNA-518a-5p has been verified
through the Real-Time PCR methods and the mi-RNA micro-error
results [25].
Mi-RNA-221/222
There have been various experiments and studies performed
and it was found that when these mi-RNAs were displaced to the
GIST48, the cells represented important effects in the various cellular
processes in association with the role of every KIT gene in the tumor
development (such as migration, cell proliferation, and apoptosis).
Therefore, mi-RNA-221/222 may be applied as an alternative
therapeutic option for GIST.
Additionally, there have been some strategies made for
overcoming the drug resistance concerns [26].
Mi-RNA-137
Using In-Silico analysis, it was revealed that the gene TWIST1, as
a key regulatory gene for the gene EMT, can be considered as a target
for mi-RNA-137.
The expression of mi-RNA-137 decreases dramatically in the
clinical samples of GIST.
Mi-RNA-494
The quantitative RT-PCR method is used for evaluation of mi-
RNA-494 expression levels, western blot for evaluating the KIT
protein expression levels and measuring by the enzyme luciferase for
evaluating the target.
The functional effect of mi-RNA-494 on the GIST882 cells (GIST
cell lines with the muted KIT gene activity) was proved by evaluating
the cells’ proliferation and the categorization of the cells activated by
fluorescence was analyzed.
The direct targeting of the KIT gene by mi-RNA-494 was shown
by reduction in the KIT gene expression after mi-RNA-494 over
expression and increase in the KIT gene expression after inhibition
endogenous mi-RNA-494 expression.
Mi-RNA-494 regulates the KIT gene through binding to two
different connection points.
The over expression induction in GIST882 reduces the expression
of downstream molecules in the kit gene signal transduction pathways
[33] consisting of the phosphor-AKT and phosphor-STAT3 [34].
Mi-RNA-494 is a negative regulator of KIT gene in the GISTs and
its over expression in the GISTs may increase the hopes for the GIST
treatment [35].
Mi-RNA-196a
This type of mi-RNA contributes in the tumors’ development and
is associated with the high-grade and metastatic tumors and those
samples having a low capability of survival and being alive in the
GIST samples.
The mi-RNA-196a gene is placed into HOX gene clusters and
the micro-error expression analysis shows that the genes HOX and
HOTAIR are up-regulated consistently in the GISTs with a high
expression of mi-RNA-196a. These findings indicate the very high
and simultaneous expression of the HOX genes with the non-coding
RNAs in the human cancers which show that the genes mi-RNA-196a
and HOTAIR are two efficient biomarkers being the treatment targets
in the malignant GIST cells.
The up-regulation of mi-RNA-196a has a strong relationship
with the high risk in the GIST developed patients. In addition, the
mi-RNA-196a over-expression is associated with the up-regulation
of the HOXC cluster genes and a non-coding RNA relating to the
metastasis in the GISTs. The mi-RNA-196a high expression has been
observed in both the small intestine and gastric GIST.
Mi-RNA-196a and HOTAIR are expressed in the GIST-T1 cells.
The micro-error results showed that mi-RNA-196a is expressed in
the high-risk GISTs significantly more than the other groups. The
micro-error data analysis for the mi-RNA-196a target genes was
computationally predicted through target scan.
In addition, mi-RNA-196a inhibits the HOXC8 gene expression
and prevents the invasion and metastasis of the breast cancer cells
[36].
Mi-RNA-196a seems to apply the opposite effects on the tumors
with various origins [37].
Mi-RNA-133b
Mi-RNA-133b is placed in the 6p12.2 area and is down-regulated
in the Bladder, Colon, Lung, and Esophagus carcinomas.
This type of mi-RNA is down-regulated in the high-grade GISTs;
in contrast, the fascin-1 mRNA is up-regulated as compared with
mi-RNA-133b. This result is consistent with the previous report
suggesting that fascin-1 may be a direct target of mi-RNA-133b.
The mi-RNA-133b expression tends to decrease in the GISTs
with the high-grades of NIH as compared to those with the grades
lower than medium and its expression level is inversely related to the
mitotic division's number.
When the mi-RNA-133b down-regulation occurs in the
cancerous cells, an up-regulation seems to occur in the target mRNA
and thus, it can involve in the oncoprotein over expression or activity.
The findings also indicated that the primary location, tumor size,
AFIP grade and genotype of the KIT gene have no relationship with
mi-RNA-133b expression level [38].
Mi-RNA-17-92
The mi-RNA-221/222 and mi-RNA-17-92 cluster members
decrease dramatically (Po0.01) in the GISTs vs. GI-LMS and the normal gastrointestinal tract control tissues. The progressed GIST
has been observed to be associated with the reduced mi-RNA-17 and
mi-RNA-20a having some genes in 13q31.3.
Over-expression of mi-RNA-17/20a/222 in the GIST cell lines
leads to the serious inhibition of the cellular proliferation, affection
on the cell cycle process, apoptosis induction, and a strong downregulated
protein in a lower level- and the mRNA levels of their ETV1
and KIT predicted target genes. The analyses reporting the enzyme
luciferase approve direct regulation of the genes KIT and ETV1 by
mi-RNA-222 and mi-RNA-17/20a, respectively.
There is a certain potential in the mi-RNA-17/20a/222 targeting
the genes KIT and ETV1. This mi-RNAs' transference as the drug
can be a potential option for managing the GISTs especially in the
patients resistant to Imatinib. Both KIT genes’ structure contains the
potential parts for connection to mi-RNA-17/20 and mi-RNA-222.
The GIST-T1 and GIST-882 cells lines are transferred as the
mimics of the mixed mi-RNA-20a, mi-RNA-17, and mi-RNA-222
(Mneg).
The mi-RNA-17-92 and mi-RNA-221/222 cluster members
distinguish the GISTs from GL-LMS [39].
Mi-RNA-125a-5p
The over expression of mi-RNA-125a-5p and mi-RNA-107 is
associated with the Imatinib’s sustainability in the GIST samples.
The over expression of mi-RNA-125a-5p inhibits the PTPN18
expression and this inhibition increases the survival capability of the
GIST882 cells being treated by Imatinib. The PTPN18 protein levels
are significantly lower in the GISTs resistant to Imatinib and have
an inverse relationship with the expression of mi-RNA-125a-5p. The
new findings show a new functional role for mi-RNA-125a-5p about
responding to Imatinib through regulating the PTPN18 in the GISTs.
The mi-RNA-125a-5p modifies the Imatinib sensitivity in the
GIST882 cells having a homozygous mutation in the KIT gene but
plays no role in the GIST48 cells having a dual mutation in the KIT
gene.
In addition, the functional role of mi-RNA-125a-5p and its
potential targets in the GIST cells’ drug resistance was examined and
the target protein expression level in the GIST clinical samples was
evaluated [40].
Mi-RNA-335 and mi-RNA-34a
The CpG islands in the mi-RNA-34a and mi-RNA-335 are
repeatedly methylated in the GIST-T1 cells and primary GIST samples
[41]. However, these CpG islands are not methylated in the normal
mode and the methylation of these areas has a direct relationship with
the target gene silence [42,43].
The transfer of the mi-RNA-34a or mi-RNA-335 molecules,
which are somewhat similar to each other, into the GIST-T1 cells,
inhibits the cell proliferation and also, mi-RNA-34a is considered as
an inhibitor of migration and invasion of the GIST-T1 cells.
One of the target genes being down-regulated through mi-RNA-
34a has been predicted to be the PDGFRA gene.
The intervening RNA knocked down for the gene PDGFRA in the
GIST-T1 cells inhibits cell proliferation and it is suggested that the
inhibitory impact of mi-RNA-34a tumor is applied by targeting the
gene PDGFRA through RNA, at least at this part [34]. PDGFRA gene
expression inhibition by mi-RNA-34a through mainly RT-PCR and
slightly GIST-T1 cells has been approved.
Mi-RNA-34a and mi-RNA-33 are considered as two candidates
among the mi-RNAs to inhibit tumorigenesis in the GIST cells and
are included in many factors silencing the genes through epigenetic
processes in the GISTs [41,44].
Figure 2
Figure 2
Endoscopic appearance of 8 mm superficial ulcer in the second
portion of the duodenum [20].
Figure 3
Table 1
Results
In this article, we have reviewed the various characteristics of the mi-RNAs effecting on the GIST disease. These characteristics include tumor inhibition and suppression, therapeutic effects, cell proliferation, cell division inhibition (in my opinion, division and proliferation make the same sense and it is better to write only one of them), migration, drug resistance, drug delivery, response to hypoxia, effect on the gene expression, capability to be methylated, metastasis ability, apoptosis ability. Certainly, every mi-RNA does not have necessarily all the above-mentioned features but the characterized features of each mi-RNA are listed in (Table 1). A mi-RNA is characteristically useful when it plays an effective role in terms of therapeutic interventions, drug delivery, apoptosis induction, and disease control. Comparing all the above-mentioned mi-RNAs, mi- RNA-21 seems to have a better interfering effect than the RNAs because it is directly involved in the inhibition of carcinogenesis. Further, it plays an effective role in treating this disease by increasing the sensitivity of the cells to Imatinib and apoptosis induction, although additional and more accurate research is required to better understand the control and mechanism of the effect of this mi-RNA.
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