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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 1  |  Page : 115-119

Evaluation of circulating miR-21 and miR-222 as diagnostic biomarkers for gastric cancer


1 Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
2 Department of Medical Biotechnology, School of Allied Medicine; Pediatric Growth and Development Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences, Tehran, Iran
3 Colorectal Research Center, Iran University of Medical Sciences, Tehran, Iran
4 Gastrointestinal and Liver Disease Research Center, Iran University of Medical Sciences, Tehran, Iran
5 Department of Anesthetic, School of Allied Medicine, Qazvin University of Medical Sciences, Qazvin, Iran

Date of Web Publication13-Mar-2019

Correspondence Address:
Dr. Reza Nekouian
Department of Medical Biotechnology, School of Allied Medicine, Iran University of Medical Sciences, Shahid Hemmat Highway, Tehran
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_592_17

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 > Abstract 


Introduction: Gastric cancer is responsible for a large number of death worldwide and its high death rate is associated with a lack of noninvasive tools in GC diagnosis. MicroRNAs (miRNAs), as gene regulators, were shown to dysregulate in different types of cancer. Moreover, it is proven that miRNAs are stable in serum/plasma, so they can be used as a potential noninvasive marker in GC diagnosis. The objective of this study is to investigate the plasma miRNA expression in GC samples compared to controls as a potential biomarker in cancer diagnosis.
Materials and Methods: Expression levels of miR-21 and miR-222 were assessed using quantitative real-time polymerase chain reaction in plasma of 30 GC patients and 30 healthy controls. Diagnostic value of selected miRNAs was evaluated using receiver operating characteristic curve. Target prediction was done using bioinformatics tools to investigate the signaling pathways and function of the selected miRNAs.
Results: Our results demonstrated that the expression levels of miR-21 and miR-222 were significantly higher in GC plasma than in the controls (P < 0.0001, P = 0.043). The sensitivity and specificity for miR-21 and in plasma were 86.7% and 72.2% and for miR-222 were 62.5% and 56.2%, respectively. Bioinformatics analysis revealed that most target genes of miR-21 and miR-222 are involved in cancer-related signaling pathway such as tumor initiation and progression.
Conclusion: Our results indicated that miR-21 and miR-222 in plasma samples can be served as a potential noninvasive tool in GC detection. Furthermore, the miRNA target prediction manifested that miR-21 and miR-222 involve in key processes associated with GC initiation and development.

Keywords: Biomarker, diagnosis, gastric cancer, microRNA, plasma


How to cite this article:
Emami SS, Nekouian R, Akbari A, Faraji A, Abbasi V, Agah S. Evaluation of circulating miR-21 and miR-222 as diagnostic biomarkers for gastric cancer. J Can Res Ther 2019;15:115-9

How to cite this URL:
Emami SS, Nekouian R, Akbari A, Faraji A, Abbasi V, Agah S. Evaluation of circulating miR-21 and miR-222 as diagnostic biomarkers for gastric cancer. J Can Res Ther [serial online] 2019 [cited 2019 Oct 18];15:115-9. Available from: http://www.cancerjournal.net/text.asp?2019/15/1/115/244469




 > Introduction Top


Gastric cancer (GC), a high prevalence cancer, is responsible for a large number of death worldwide.[1] The high mortality rate in GC is partially associated with a lack of noninvasive tool for GC detection at early stages.[2] Better prognosis and reduced mortality rate of GC depend on the tumor stage at the time of diagnosis. On the other hand, delay in the malignancy detection leads to cancer progression and short-time survival.[3] Accordingly, there is an urgent need for detection of novel biomarker that can be used in early diagnosis and prognosis of cancer.[4],[5]

MicroRNA (miRNA) is an important subcategory of small noncoding RNA with 18–24 nucleotides in length.[6] They can involve in a lot of cellular processes through gene expression regulation at the posttranscriptional level.[7] A large number of studies have been shown that miRNAs can act as oncogene or tumor suppressor in various cancer-related signaling pathways including abnormal cell proliferation and tumor angiogenesis.[8],[9],[10],[11]

Stability of circulating miRNAs along with aberrant expression of these small noncoding RNA in GC has clearly demonstrated in several studies which represents their potential applications in cancer diagnosis and prognosis.[12],[13],[14] The bioinformatic studies demonstrated that miR-21 and miR-222 play important roles in GC-related cell signaling processes. Accordingly, we hypothesized that the dysregulation of these miRNAs can be used as a potential diagnostic biomarker in GC detection.

The objective of this study was to investigate the plasma miRNA expression in GC patients compared to healthy controls as a potential diagnostic biomarker.


 > Materials and Methods Top


Subjects

A total of 30 gastric patients and 30 healthy adult volunteers participated in this study. [Table 1] shows some clinicopathological characteristics of GC patients. University Ethics Committee approved the written informed consent that was taken from all of the participants. Sample collection was performed before any cancer treatment including chemotherapy, radiotherapy, and surgery.
Table 1: Clinicopathological characteristics of gastric cancer patients and controls

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Samples

Peripheral whole blood was collected in ethylenediaminetetraacetic acid tubes (3–5 mL per tube). Each blood sample was immediately centrifuged, at 1500 G for 15 min, after collection. The upper solution (supernatant) was then transferred into RNase-free Eppendorf tubes. For elimination of cell-free nucleic acid, second centrifugation was performed at 10,000 G for 5 min at 4°C and plasma aliquots were stored at −80°C until further analysis.

RNA extraction

Total RNA isolation was performed from 200 μl of the thawed plasma using Qiagen miRNeasy Serum/Plasma Kit (Qiagen Cat # 217184). 3.5 μL miRNeasy Serum/Plasma Spike-In Control (Qiagen Cat # 219610) was added into the tube containing the plasma sample in the early steps of extraction protocol. In the last step of the protocol, RNA was eluted in 14 μl of Elution solution (RNase-free water) according to the manufacturer's instructions. Determination of RNA purity and its concentration was performed by NanoDrop ND-2000 Spectrophotometer (Thermo fisher, Germany).

Quantification of microRNA by reverse transcription real-time polymerase chain reaction

Expression levels of mature miR-21 and miR-222 were determined by quantitative real-time polymerase chain reaction (qRT-PCR) using the specific primers [Table 2], and each reaction was done in duplicate, as previously described.[15],[16] Extracted RNA was used for polyadenylation reaction and first strand cDNA synthesis using miScript II RT Kit (Qiagen, Cat # 218,161) according to the manufacturer's instructions. After reverse transcription reaction, 10 μl reaction volume (containing, 2 μl of cDNA as a template) was prepared for real-time PCR using miScript SYBR® Green PCR Kit (Qiagen, Cat # 218073) by an Applied Biosystems real-time Thermal Cycler. Fold change values of miRNAs in this study were calculated relative to exogenous spike-in cel-miR-39, as an internal control gene, by the method.[17],[18]
Table 2: Primer sequences used for quantitative real-time polymerase chain reaction in this study

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Target prediction of human microRNAs and their function

Several database associated with target prediction of miRNAs has been used for understanding the molecular function of the selected miRNA in cancer signaling pathway. MiRNA targets databases such as miRanda (http://www.microrna.org/microrna/home.do/), miRTarBase (http://mirtarbase.mbc.nctu.edu.tw/), miRDB (http://mirdb.org/), PicTar (http://pictar.mdc-berlin.de/), MiTarget (http://cbit. snu.ac.kr/~miTarget), and miRWalk (http://www.umm.uni-heidelberg.de/apps/zmf/mirwalk/index.html) containing information about miRNA target genes.

Statistical analysis

Data analysis was completed using the IBM SPSS Statistics, United states. The Kolmogorov–Smirnov test, as a normality test, was used for assessment of the normal distribution. Fold change of miRNAs between patients and normal control was compared with Student's t-test or Mann–Whitney U-test. P < 0.05 was considered as statistically significant. Potential diagnostic value of plasma miR-21 and miR-222 in discrimination between cancer patients from healthy individuals was determined by receiver operating characteristic (ROC) analysis.


 > Results Top


Population characteristics

In total, 50 individuals containing 30 Iranian GC patients and 30 controls were recruited in this study. No significant differences were observed between the GC patients and controls in the distribution of age and gender.

MicroRNA expression level in the plasma samples

Expression levels of plasma miRNAs were quantified by qRT-PCR using Spike-In Control (miR-39) as a normalization control. The results of the present study demonstrated that expression level of circulating miR-21 was significantly higher in GC patients than in healthy individuals [P < 0.0001; [Figure 1]a. The Mann Whitney U-test done to compare the relative expression of miR-222 showed that the plasma level of this miRNA was also increased in cancer samples [P = 0.043; [Figure 1]b.
Figure 1: Box plots of the plasma expression level of miR-21 (a) and miR-222 (b) in GC patients and controls

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Application of cell-free microRNAs in gastric cancer diagnosis

To evaluate the potential application of circulating miRNA as a diagnostic biomarker, further analysis was done for measurement of specificity and sensitivity of plasma miRNAs using ROC curve analysis.

Circulating miR-21 with an area under curve (AUC) of 0.893 (95% confidence interval [CI]: 0.755–1.000; P < 0.0001) could serve as a potential biomarker for GC diagnosis with the sensitivity of 86.7% and the specificity of 72.2% at the cutoff of 3.95 [Figure 2]a. While data analysis demonstrated that the AUC value was 0.747 (95% CI: 0.550–0.943; P = 0.044) for miR-222 in plasma samples, with the sensitivity of 62.5% and the specificity of 56.2% at the cutoff of 4.31 [Figure 2]b.
Figure 2: Receiver operating characteristic (ROC) curve analysis of miR-21(a) and miR-222 (b) in plasma samples

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Target prediction and function analyses of miR-21 and miR-222

Target prediction of human miR-21 and miR-222 was performed using miRNA databases www.mirdb.org/ to understand the roles of these miRNAs in GC. The results of the bioinformatic analysis demonstrated that miR-21 targets several genes by a range of target scores from 71 to 99; special AT-rich sequence-binding protein-1 (SATB1), T-lymphoma invasion and metastasis-inducing protein 1 (TIAM1), programmed cell death protein 4 (PDCD4), phosphatase and tensin homolog (PTEN), apoptotic protease activating factor 1 (APAF1), metalloproteinase inhibitor 3 (TIMP3), transforming growth factor beta 1 (TGF-β), and pleomorphic adenoma Gene 1 (PLAG1). Also, it was revealed that miR-222 potentially targets important genes including, SDC2, PRKX, RB1, and PPP2R5E.


 > Discussion Top


It is well known that genetic and epigenetic alterations can affect many tumor-related genes and lead to tumor formation and cancer progression.[15],[16],[17] Recent studies have focused on tumor-specific alterations in circulation to detect the cell-free blood-based biomarker as a noninvasive tool for cancer diagnosis.[18],[19]

GC is one of the most prevalent malignancies worldwide with 754,000 mortality rate annually.[20] The high mortality rate is mainly associated with a lack of effective tool for GC detection at an early stage.[2] For most cancers, blood-based proteins have been proven and widely used as biomarkers in clinical diagnosis. Unfortunately, the circumstance is quite different for GC. Common tumor biomarkers such as CA125, CA199, and carcinoembryonic antigen have exhibited poor diagnostic value in GC.[21] Therefore, there is an urgent need to discover effective biomarkers for GC detection.

MiRNAs, a subcategory of noncoding RNA, are gene - regulatory molecules that can suppress their target genes at the posttranscriptional level.[22] Accordingly, it has been known that miRNAs are involved in the various carcinogenic signaling process such as abnormal cell proliferation, cancer progression, and tumor development as well as cell invasion and tumor metastasis.[2],[23] In addition to being highly stable in body fluids, miRNAs are also readily detectable in serum/plasma, so these small RNAs can be used as a potentially noninvasive clinical biomarker for various cancer diagnosis.[24],[25],[26] In the current study, we investigated the expression levels of miR-21 and miR-222, as GC-related miRNAs, in GC plasma samples compared to healthy controls. According to our data, the plasma expression level of miR-21 (P < 0.0001) and miR-222 (P = 0.043) were higher in GC patients than in healthy controls. Furthermore, ROC curve for miRNAs of interest showed circulating miR-21 with an AUC of 0.893 (95% CI: 0.755–1.000; P < 0.0001), and miR-222 with an AUC of 0.747 (95% CI: 0.550–0.943; P = 0.044) can be served as a potential biomarker for GC diagnosis.

Consistent with previous findings about the expression level of miR-21 in other types of cancer, we also found that miR-21 could be significantly overexpressed in GC.[27],[28],[29] MiR-21, as an important oncomiR, induced several related cell signaling pathways including cell growth, tumor formation as well as angiogenesis and metastasis.[29],[30] MiR-21 involves in abnormal cancer-related processes by targeting of several genes such as SATB1, TIAM1, PDCD4, PTEN, APAF1, TIMP3, TGF-β, and PLAG1.[31],[32],[33]

SATB1 is expressed in thymocytes, which play important roles in proliferation, differentiation, maturation, and apoptosis of T-cells.[31],[34] SATB1 could positively control cyclin-dependent kinase 4 gene (CDK4),[35] while SATB1 can negatively regulate the expression level of multiple tumor suppressor 1 (p16),[36] an inhibitor of cell cycle progression, and Fas-associated protein with death domain,[37] as a facilitating apoptosis gene. SATB1 can also promote cell cycle progression and proliferation, inhibit liver cancer cell apoptosis and induce epithelial-mesanchymal transition (EMT) by regulating the expression of these genes, promote the growth and metastasis of liver cancer cells, and provide potential promoting factors.[38]

PDCD4, an important tumor suppressor gene, is able to suppress cell proliferation through inhibiting a mitosis-promoting factor, so called cyclin-dependent kinase 1 (CDK1/cdc2), through transcriptional induction of p21 which is known as a CDK inhibitor.[39] Yang et al. in 2006 showed that suppressing mitogen-activated protein kinase kinase kinase kinase 1 (MAP4K1) through PDCD4 can lead to inhibition of tumor invasion.[40]

On the other hand, several studies have also showed that miR-21 is involved in several cancer-related signaling pathways by directly targeting PTEN and TGF-β as target genes.[41] These genes play important roles in regulation of cell apoptosis, proliferation, and migration.[42],[43] There are few studies on the expression level of miR-222 in GC. PTEN and RECK, as key tumor suppressor genes, involve in a number of cellular functions, including inhibition of abnormal cell proliferation and cell invasion, as well as induction of apoptosis. Hence, the suppression of these two tumor suppressor genes as target genes of miR-222 can lead to cancer initiation, progression, and development.[44],[45],[46]

However, miRNA as a novel prognostic and diagnostic biomarker is high stable than other types of RNA molecules, but its stability relative to other diagnostic blood markers such as protein or DNA biomarker is less.[47] Hence, a number of measures should be done to prevent miRNAs from degradation in the blood sample.[48] Overall, our findings showed that miRNAs were significantly upregulated in plasma samples of GC patients, and these circulating markers can be used as a noninvasive tool for discriminating of GC patients from healthy individuals.


 > Conclusion Top


Our result demonstrated that expression levels of circulating miR-21 and miR-222 in GC patients' sample were significantly higher than those in noncancerous samples. Moreover, miRNA target prediction by bioinformatics tools manifested miR-21 and miR-222 mainly involved in key processes associated with GC initiation and development. Altogether, this data provide strong support for potential application of miR-21 and miR-222 in plasma samples as a minimally invasive tool in GC detection.

Acknowledgment

The authors would like to thank all participants through this study.

Financial support and sponsorship

This study was financially supported by Iran University of Medical Sciences.

Conflicts of interest

There are no conflicts of interest.



 
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