TARGETED microRNA PROFILING IN GASTRIC CANCER
WITH CLINICAL ASSESSEMENT
Pehlevan Ozel H, Dinç T, Tiryaki RS2, Keşkus AG, Konu O, Kayilioglu SI, Coşkun F
*Corresponding Author: Tolga Dinç, M.D., Associate Professor, Department of General Surgery,
Health Sciences University, Ankara City Hospital, Üniversiteler Mahallesi 1604. Cadde No: 9 Çankaya/
Ankara/Turkey. Tel./Fax: +90-312-552-60-00. Intercom: 121514. Mobile: +90-532-481-22-75. Email:
tolga_dr@hotmail.com
page: 55
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DISCUSSION
Currently, an increasing number of studies are being
conducted on the biogenesis of gastric cancers, and
effective diagnostic methods and treatments are investigated,
helping understand the disease progression at the
molecular level [25]. The miRNAs are relatively novel
molecules with their poorly understood regulatory mechanisms
and molecular interactions and can provide novel
opportunities for gastric cancer diagnosis and prognosis
[27,28]. Current knowledge states that miRNAs play active
roles in cancer biogenesis with tumor-suppressive or
oncogenic activities via modulating targets involved in
carcinogenesis and tumor progression [2,3]. The prognoses
and treatment responses for cancers differ, based on
demographics, including the geography and ethnicity, as
well as molecular characteristics. Several studies that exist
in the literature for gastric cancer use paraffin-embedded
formalin fixed tissue [29], and thus, our study using an
independent cohort of freshly frozen tumor-normal pairs
adds to the existing literature, using gastric cancer paired
miRNA biomarkers obtained from cancer-adjacent normal
fresh tissue collection. We found that miR-375-3p, miR-129-5p and miR-
34c-5p decreased significantly in gastric cancer, while
miR196a-5p, miR376c-3p and miR-767-5p exhibited the
most significant downregulation of expression. Our findings
could provide good candidates for further testing as
biomarkers in different gastric cancer cohorts. The present
study also showed that the expression levels of miRNAs
varied more in the adjacent normal tissue in comparison to
paired tumors, supporting the notion that miRNA expression
could be regulated in a stronger manner in cancerous
tissue in accord with the literature [30].
Although the sample size limited the scale of our
clin-icopathological assessments, we found associations
with age and the number of metastatic lymph nodes. It
was observed that lower miR-662 expression levels were
significantly associated with increased age, and the expressions
of miR-129-3p and miR-34c-5p correlated with the
number of metastatic lymph nodes in the gastric cancer
tissues. Indeed, previous studies have identified a correlation
between miRNA levels and age [31] and invasion
into lymph nodes [32]. Our findings provide novel miRNA
candidates associated with these selected clinical parameters
in gastric cancers.
One of the miRNAs we identified as being downregulated,
miR-375-3p (2q35), first found in pancreatic
β cells playing a role in pancreatic organogenesis and β
cell function [30], has been shown to be decreased in
laryngeal, esophageal, gastric, hepatocellular cancers and
pancreatic ductal adenocarcinoma, while increasing in
hepatitis B virus (HBV)-positive hepatocellular cancer,
as well as lung and breast cancers [10-11,33-35]. The
miR-375 targets JAK2, a cytokine signaling pathway
molecule, leading to cell proliferation in gastric cancer
[11]. The first article showing the relationship between
miR-375 and gastric cancer indicated that it has a direct
effect on PDK-1 and 14-3-3 ζ(YWHAZ) and the caspasedependent
apoptotic pathway, leading to cancer development
via DNA methylation and histone deacetylation [10];
miR-375 also modulates JAK2/STAT3 signaling pathway
[36]. Accordingly, miR-375 is a tumor suppressor miRNA
whose downreg-ulation can be important for determining
the degree of cancer progression. Other mechanisms are
arising for the actions of miR-375 via its correlation with
increased levels of Recepteur d’Origine Nantais (RON), a
tyrosine kinase receptor [37]; miR-375 targets SLC7A11
directly and triggers ferroptosis [38]. These studies also
indicate that modulation of target gene expression by
miR-375 may also be considered for developing novel
treatments for gastric cancer [33]. In the present study,
we support the tumor suppressive role of miR-375 in our
independent and paired cohort, in a manner consistent
with the literature [10-12].
Previous studies have also shown that miR-148a-3p is
downregulated in gastric cancer tissues with a diagnostic
significance. miR-148a-3p has been reported as having
an association with TNM staging and lymph node metastasis
[39]. A previous study using tumor-normal pairs
from gastric cancer patients has identified miR-148-3p as a
downregulated biomarker [40]. Although the miR-148a-3p
value exhibited a trend for downregulation in our study,
there was no statistically significant result (p = 0.325)
due to observed variability among patients. Potentially,
this shows that the molecular subtype composition within
and between patient cohorts could affect the significance
of this miRNA in gastric cancer diagnosis. In our study,
miR-148a-3p level was relatively lower in patients encoded
with GCM-01, GCM-03, GCM-04 and GCM-06,
who might represent different molecular characteristics
from other patients and warrants further study.
On the other hand, miR-196a-5p is known to be effective
in gastric cancer diagnosis/prognosis in the literature
and shown to achieve this via its overexpression [14,41].
miR-196a is in a genomic region where the homeobox
(HOX) genes are located and exerts an effect on these
genes, along with high mobility group A2 (HMGA2), annexin
A1 (ANXA1) and keratin 5 (KRT5) [42]. It has also
been reported to be upregulated in other cancers, such as
breast, esophageal and colorectal cancers, and leukemia
[42]. In the present study, the level of miR-196a appears to
be significantly downregulated as in acute lymphoblastic
leukemia (ALL) and melanoma. Previous gastric studies of
miR-196a were conducted in Far Eastern countries, such
as China and Japan. This difference in expression in the
present study may have resulted from geography, ethnicity
as well as cohort specific molecular subtype composition,
however, more studies are needed to confirm direction of
this miRNA in gastric cancer using larger cohorts.
The literature also presents contradictory findings
about miR-376c-3p, although only a few studies have
investigated this miRNA [16,17]. Our findings supported
that miR-376c was highly significantly downregulated in
cancerous tissue, while there was a significant relationship
between miR-376c-3p and smoking (p = 0.043).
miR-129-3p, another miRNA known to be downregulated
in gastric cancer, exerts its effect on cell proliferation
by acting through its target cyclin-dependent kinase 6
(CDK6) [18]. In the present study, we confirmed the decrease
in the miR-129 level in the paired cancerous tissue
as compared to that in the normal tissue, consistent with
previous reports. In addition, we found that the number
of metastatic lymph nodes exhibited a significant correlation
with the miR-129 level. Previous studies identified an
upregulated, metastasis associated long noncoding RNA
target (AC130710) as one of the targets of miR-129-5p in gastric cancers [19] as well as significant association
between miR-129 levels and clinical parameters such as
tumor size and lymph node metastasis, which support
our findings.
miR-34c-5p has been frequently studied in the literature
as it plays an important role in cancer biogenesis with
its effect on DNA methylation and shows downregulation
in gastric cancer [6]. In the present study, we found that
miR-34c was significantly associated with both the number
of metastatic lymph nodes and the lower expression
in cancerous tissue, consistent with previous reports [20].
miR-662 is best known for its role in the immune
response against viruses and cancerous tissues by affecting
the NLRC5 gene [43]. miR-662 upregulation could also be
a factor responsible for distant metastasis in lung cancer
[44]. To the best of our knowledge, no previous studies have
investigated the relationship between miR-662 and gastric
cancer. In the present study, the miR-662 in cancerous tissue
showed downregulation with a p value only approaching
significance due to variance observed among patients (p =
0.079). Future studies need to be performed using larger
patient cohorts to help understand the source of this variability
of expression among subtypes of gastric cancers.
Few studies have investigated miR-767-5p in the literature;
upregulation of miR-767-5p through hypomethylation
is thought to play a role in tumor development [45] as
in melanoma [46]. There is no study other than that recently
published by Geng et al. [22], demonstrating an association
between gastric cancer and low levels of miR-767-5p.
In our paired cohort, we also showed that miR-767, was
highly significantly downregulated in cancerous tissues (p
= 0.001). Although recent studies show that overexpression
of miR-767-5p is associated with cell proliferation in
multiple myeloma, hepatocellular carcinoma and prostate
cancer [47-50], the findings in this study and Geng et al.
[22], point to lower miR-767-5p in gastric cancer when
compared with paired normal tissue as in glioma [51]
and more recently in gastric cancer [22]. These implicate
that the same miRNA may function in the opposite directions
in different cancers and future studies are needed
to understand the mechanisms at work. Moreover, the
demonstration of the similarity between the expression of
miR-375-3p, which is known to be downregulated based
on the literature, [10-12] and miR-767-5p in patients supports
this statistical significance.
In conclusion, to the best of our knowledge, this is the
second report of miR-767 and its downregulation, while
the first analysis on miR-662 expression levels in gastric
cancer tissues. More importantly, our results implicate
for the first time, differential expression of two miRNAs,
namely, miR-662 and miR-376c-3p, respectively, with
age and smoking in gastric cancer. We also associate the
increased number of metastatic lymph nodes with the
downregulation of gastric cancer specific miRNAs.
Our study showed that miR-375, miR-196a, miR-
376c, miR-129, miR-34c and miR-767, all downregulated,
may be used as biomarkers in development of diagnostic
tools for gastric cancer. Moreover, miRNAs in cancerous
tissues are likely to be expressed in a narrower range, and
thus, could be under a stronger control of genomic/transcriptomic
elements based on previous research. This could
also be due to presence of higher cellular heterogeneity in
the normal adjacent tissues of gastric cancers. The present
study may lead to the understanding of the biogenesis of
gastric cancer via finding targets of the miRNAs studied
and to the discovery of novel molecular targets for treatment.
However, further genetic, and functional studies on
this subject with larger sample sizes are needed.
Acknowledgments. Language and grammar editing
was performed by English Proofreading, Scientific Paper
Editing & Proofreading Service.
Declaration of Interest. The authors report no conflicts
of interest. The authors alone are responsible for the
content and writing of this article.
Funding. This study was supported by TUEK (Board
of Education and Expertise in Medicine [Grant #2017-
0057]). Funding source had no involvement in the conducting
or reporting process of this study.
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