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ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 8  |  Page : 132-137

Upregulation of miR-371-373 cluster, a human embryonic stem cell specific microRNA cluster, in esophageal squamous cell carcinoma


1 Golestan Research Center of Gastroenterology and Hepatology, Department of Human Genetics, Golestan University of Medical Sciences, Gorgan, Iran
2 Department of Molecular Genetics, Faculty of Biological Sciences, Tarbiat Modares University, Tehran, Iran
3 Department of Pathology, Faculty of Medicine, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran

Date of Web Publication26-Mar-2018

Correspondence Address:
Nader Mansour Samaei
Golestan Research Center of Gastroenterology and Hepatology, Department of Human Genetics, Golestan University of Medical Sciences, Gorgan
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.171361

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 > Abstract 


Aims: Esophageal squamous cell carcinoma (ESCC) is the most common subtype of esophageal cancer in Iran. MicroRNAs (miRNAs) are a class of noncoding RNAs that are found to be involved in different processes and can play a role in tumorigenesis and result in cancer. MiR-371, miR-372, and miR-373 are a gene cluster that is located in the region of the human chromosome of 19q13.4. They are specifically expressed in human embryonic stem cells (ESCs) and involved in the maintenance of the stemness features through regulating the expression of certain key genes and signaling pathways. The present study investigated the potential expression of miR-371–373 cluster in tumor and nontumor tissues of ESCC.
Materials and Methods: The expression level of miR-371–373 cluster was analyzed in paraffin-embedded tissues of tumor and tumor margin in 36 patients with ESCC. Total RNA was isolated and the miR-371–373 clusters were quantified with quantitative real-time-polymerase chain reaction expression analysis. Computed tomography analysis (2–ΔΔCT) and t-test were used to determine the relationship between the characteristics of the tumor and nontumor tissues. Statistically, P value of <0.05 were considered significant. Data analysis was performed using SPSS 16.
Results: We provided miR-371, miR-372, and miR-373 upregulation evidence significantly with 14.36, 26.9, and 21.1-fold in esophageal cancer cells compared with their adjacent normal cells (P < 0.05), respectively. In addition, evaluation of these genes expression in various grades didn't show a significant difference.
Conclusion: Our findings support the hypothesis that these miRNAs might play a role in tumorigenesis in esophageal cancer.

Keywords: Embryonic stem cell, esophageal cancer, miR-371-373 cluster


How to cite this article:
Ghasemi M, Samaei NM, Mowla SJ, Shafiee M, Vasei M, Ghasemian N. Upregulation of miR-371-373 cluster, a human embryonic stem cell specific microRNA cluster, in esophageal squamous cell carcinoma. J Can Res Ther 2018;14, Suppl S1:132-7

How to cite this URL:
Ghasemi M, Samaei NM, Mowla SJ, Shafiee M, Vasei M, Ghasemian N. Upregulation of miR-371-373 cluster, a human embryonic stem cell specific microRNA cluster, in esophageal squamous cell carcinoma. J Can Res Ther [serial online] 2018 [cited 2019 Jun 17];14:132-7. Available from: http://www.cancerjournal.net/text.asp?2018/14/8/132/171361




 > Introduction Top


Despite currently available therapies, esophageal cancer presents symptomatically in the late stages of the disease, and therefore has a poor prognosis.[1] Adenocarcinoma and squamous cell carcinoma (SCC) are two major histological types of cancer [2],[3] and their prevalence is associated with specific geographic dispersion.[1] SCC type includes more than 90% of esophageal carcinoma in Iran.[4]

Recently, researches show that the surplus of cancer stem cells in infected tissues after therapy can result in therapeutic resistance and recurrence of disease in patients.[5],[6],[7] In addition, according to the cancer researches, microRNA (miRNA) expression cause cellular changes in stem cells and these cells turns in to the cancer stem cells.[8] With this knowledge, we are looking for types of miRNAs which may have an effect on cancer progression and recurrence in the esophagus.

MiRNAs are a class of noncoding single-stranded RNAs that consist of approximately 21–23 nucleotides. They have two separate processing steps in the nucleus and cytoplasm to convert into mature miRNAs.[9],[10] miRNAs can play a role in gene expression regulation through different cellular processes such as development, differentiation, and apoptosis [11] and most of evidence suggest that expression alterations of miRNAs associated with a variety of diseases such as cancer and show tumor-specific expression. MiRNAs target RNAs and can be used as recommended targets for therapeutic or diagnostic purposes.[12],[13]

MiR-371, miR-372, and miR-373 are a set of miRNA genes which are located near each other in 19q13.4 position.[14] Members of the miR-371–373 cluster are the most abundant miRNAs in human embryonic stem cells (ESCs). Functionally, they regulate self-renewal and pluripotency processes and, therefore, represent a major regulatory role in the stemness maintenance of ESCs.[15] Furthermore, studies revealed that these miRNAs can control signaling pathways such as wnt/B-catenin pathway and result in self-renewal of stem cells and their oncogenesis of various tissues.[16],[17],[18],[19] Recently, some cancers showed increased expression of this cluster. Malignancies are associated with the increased expression of these miRNAs in numerous cancers such as liver, lung, tongue, colon cancer stem cells, and germ cells through increasing cell division and inhibition of apoptosis.[20],[21],[22],[23]

In the primary data obtained from Shafiee et al.[24] miRNA profiling in esophageal squamous cell carcinoma (ESCC) that have not been published yet, the three miRNAs miR-371, 372 and 373 revealed high expressions of more than 100 times. In addition, upregulation of miR-373 has been found in the profiling of miRNAs in ESCC, which is implemented by Lee et al., 2009.[25] In conclusion, based on these findings and with regard to critical role of miR-371–373 cluster in stem cell, we analyzed the expression of all of the members in this cluster among ESCC tissue samples of Iranian patients compared with adjacent nontumor samples for the first time to verify expression alterations of these miRNAs in ESCC.


 > Materials and Methods Top


Patients and clinical samples

A total of 36 formalin-fixed paraffin-embedded tissue samples of patients with ESCC were collected from the archives of hospitals. For further study the samples were stained with hematoxylin and eosin and examined by expert pathologists to validate the tumor and nontumor areas as well as the histopathological criteria of each sample.

Tumor and nontumor areas in paraffin blocks of each pair were carefully macro dissected and transferred to an RNase free micro centrifuge tube for RNA extraction. Other information includeing age and gender were obtained from hospital archives. Ethical approval for data collection was obtained and the project was approved by the Ethics Committee of Golestan University of Medical Sciences (Code of Ethics: 35619112276, Date: 3/18/2013).

RNA extraction

Samples deparaffinized by xylol and alcohol and digested with proteinase K solution (Fermentas, Lithuania). Incubation in PK buffer (1 mM EDTA, 1 mM NaCl, 5 mM Tris-HCl, pH 8) supplemented with 10 mg/ml of proteinase K for 3 h at 54°C. Then RNA extracted with a trizol solution (invitrogen, USA) according to the manufacturer's instructions. The concentration and purity of extracted RNA was determined based on the density of 260 nm with PicoDrop. Quantitative analysis of complex miR-371–373 performed with quantitative real-time-polymerase chain reaction (qRT-PCR).

Complementary DNA synthesis and quantitative real-time polymerase chain reaction

1.5–2ng of total RNA was subjected to qRT-PCR. In order to design primers and evaluate miRNAs expression, we used PARSGENOME MiR-Amp Kit that contains three stages: In the first stage, polyA enzyme was added to increase the length of miRNAs. Then, the first-strand cDNA was synthesized with specific designed primers by PARSGENOME company. Finally, it was amplified with ABI-7300 Real Time system and cybr-green PCR kit.

PCR of genes included an initial denaturing cycle at 95°C for 3 min, followed by 40 cycles of amplification consisting of denaturation at 95°C for 5 s, 63°C to 15 s and extension 72°C to 30 s cycles of amplification. The identity of PCR products confirmed on the agarose gel 3%, stained with sybr safe, and visualized under ultraviolet light. Relative gene expression was calculated using the standard curve methodall measurements were performed in triplicates. The Mir-16 was used as an internal control and to standardize the samples. In addition, no reverse transcription control used to detect any potential nonspecific amplification of genomic DNA.

Statistical analysis

We used excel application for expression analysis. Results analyzed with performing Student's t-test. The SPSS software (SPSS Inc., USA), version 16.0 used for statistical analyzes and the P < 0.05 considered as statistically significant. Receiver operating characteristics (ROC) curve was plotted to evaluate the suitability of miR-371–373 cluster expression to discriminate the tumor and nontumor state of the samples. In addition, the correlation between miRNAs were investigated with Pearson test.


 > Results Top


MiR-371-373 cluster includes miR-371; miR-372 and miR-373 are up-regulated in esophageal squamous cell carcinoma

MiRNA-371–373 of ESCC evaluated in 36 tumor samples and 36 samples of tumor margins as their controls. The clinical features of the SCC patient samples are summarized in [Table 1]. Results showed increased expression of miRNAs 371,372 and 373 with 14.36, 26.9, and 21.1-fold in tumor tissues compared with normal tissue margins of tumors with P < 0.05, respectively [Figure 1]a. There is no evidence of a difference between tumor and nontumor samples based on age and gender. In addition, we compared the expression level of this cluster in the samples with high and low grade and did not find any significant difference between these groups [Figure 1]b. This suggested that those miRNAs are over expressed in the early stage of esophageal cancer tumorigenesis. Gene expression analysis performed by real time system. A unique melting curve without primer dimer or other specific product is shown [Figure 2]a and [Figure 2]b. Then PCR products electrophoresed with agarose gel 3% and showed a band of 61bp for miR-371 and 62 bp for miR-372 and miR-373.
Table 1: Demographic and clinical features of patients with esophageal cancer

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Figure 1: (a) The variation of miR-371–373 expression in esophageal tumor tissue compared with tumor tissue margins revealed that all of tree genes miR-371 (14.36-fold), 372 (26.9-fold) and 373 (21.1-fold) up-regulated in EC (Esophageal Cancer). (b): Variation of the expression of miR-371–373 in grades of EC disease according to the folding

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Figure 2: (a) Melting curve graphs corresponding to the genes of miR-371–373 and miR-16. A unique melting curve without primer dimer or other specific product is shown. (b): Ct chart related genes miR-371–373 and miR-16

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MiR-372 and miR-373 showed close expression patterns in esophageal squamous cell carcinoma

Pearson's test used to determine the relationship between genes expression of miR-371–373 cluster members. The linear correlation of genes expression is shown in [Figure 3]. It is characterized by the expression of miR-372 and miR-373 in a significant linear relationship (P < 0.001, R = 0.744).
Figure 3: Linear curve relationship between the expression of miR-372 and miR-373 expression, which indicates that two microRNAs simultaneously increases linearly (P < 0.001, R = 0.744)

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MiR-371-373 expression in patients' clinicopathological data

We used ROC analysis to evaluate the suitability of miR-371–373 cluster expression. Three miRNAs for the ESCC patients and the healthy controls yielded the following values in the area under the curves (AUCs): miR-371 (0.56); miR-372 (0.65); miR-373 (0.62). MiR-372 has the largest AUC value in this cluster members (65%; P= 0.02); [Figure 4].
Figure 4: Receiver operating characteristics curve for miR-371–373. Area above 0.5 with P= 0.02 for miR-372 represents the good accuracy in the evaluation of tumor

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 > Discussion Top


Cancer stem cells are a small subpopulation of cancerous cells which were identified in a variety of tumors. They are capable of self-renewal, differentiation, and tumorigenesis. Recently, these features are found to be important processes which are controlled by miRNAs.[26],[27]

MiR-371–373 cluster members are the most abundant miRNAs in ESCs. Studies showed that this cluster is an important regulator of cellular and molecular pathways in different cells.[28] However, their potential role in pluripotency induction in somatic cells and therefore in cancer stem cells generation and initiation of tumorigenicity are not found. Thus, in this study, we evaluated a potential alteration in the expression of miR-371–373 cluster, the main regulatory miRNAs in reprogramming and pluripotency pathways, in esophageal cancer.

In this study, we demonstrated that all of miR-371–373 cluster members are up-regulated in esophageal tumor samples compared to tumor margin samples. The results are presented in [Figure 2]. Significant increase in miR-371, miR-372, and miR-373 (P < 0.05), indicates that there is a relationship between these miRNAs and tumor and a possibility of their effectiveness on common targeted genes revealed to molecular pathways in esophageal cancer. According to some researches about miRNAs, we found that each one of these cluster members can play a role in several types of cancers through targeted genes which are verified in biological researches.[25],[29],[30] Based on reliable resources such as miRWalk and miRBase,[31] we found that there are at least four common targeted genes in these miRNAs [Table 2].
Table 2: Some validated common targets for all members of miR-371-373 cluster involve in initiation and/or progression of cancer according to miRWalk database

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P53 and LATS2 tumor suppressor genes are identified as critical genes in esophageal cancer tumorigenesis. These genes are found to be common targeted genes of miR-371–373 cluster members in other cancers.[32] In addition, LATS2 is the serine/threonine protein kinase that interacts with a negative regulator of p53 and may function in a positive feedback loop with p53 that responds to cytoskeleton damage.[33] Already, Ishizaki et al. have demonstrated a direct impact of LATS2 gene on the esophageal cancer.[34] However, we suggest that these genes are possible targets of miRNAs cluster in esophagus.

ME1 gene encodes a cytosolic NADP-dependent enzyme that generates NADPH for fatty acid biosynthesis. This enzyme links the glycolytic and citric acid cycles. The increased expression can result from elevated levels of thyroid hormones or by higher proportions of carbohydrates in the diet.[35] Suh et al. found that high expression of this gene in ESCs may be linked with the theory of cancer stem cells.[36] Recently, Zhao et al. found that stem-like cell population can play an important role in metastasis and resistance to chemotherapy in patients with esophageal cancer.[18] Thus, increased expression of this cluster may affect the survival of cancer stem cells.

In addition, miR-371–373 cluster may turn off RRBP1 gene. This gene encodes a ribosome binding protein of the endoplasmic reticulum (ER) membrane. Studies suggest that this gene plays a role in ER proliferation, secretory pathways, secretory cell differentiation, and mediation of ER-microtubule interactions. RRBP1 gene can play a role in the differentiation of secretory cells.[37] On the other hand, lining secretory cells exist in the esophagus and they lose secretory function in cell transformation. Accordingly, the RRBP1 gene is considered as a possible target of this miRNAs cluster. The increased expression of this gene has been proven in breast and lung cancer.[38],[39] According to the same embryonic origin of the lung and esophagus,[40] it is possible that these genes play a role in cancer of esophagus.

Members of the cluster located in a common chromosomal region of chromosome on 19q13.4 near each other.[14] Molecular changes in this region may have an effect on the expression of this cluster and therefore may play a role in tumor angiogenesis in esophageal cancer and introduce it as a genomic region that is revealed to esophagus cancer.

The study suggested that increased expression of miR-371–373 cluster can play a role in tumorigenesis through effect on critical genes of cell cycle, such as CDKs which include cdk2, cdk4, and cdk6. It is reported that CDKs are the targeted genes of this cluster members which can cause malignant progression through interrupting cell cycle and differentiation of cells.[41]

We investigated all members of miRNA-371–373 and demonstrated that they up-regulated but gene increase of miR-372, 373 was more evident than of miR-371. On the other hand, the linear Pearson test showed a positive relationship between increased expressions of miR-372 and miR-373 together. Lichner et al. showed that the miR-290–295 cluster is Murine homolog of miR-371–373 cluster. MiR-371 is changed during evolution compared to its murine homolog miR-290 in 74 base pair while miR-372 and miR-373 are homologous respectively for miR-294 and miR-291-a of murine yet.[42] According to this study, it seems that less expression level of miR-372 compared to other members may be due to the difference of ancestral origin of miR-371. This gene may play a role in different carcinogenic pathways. In addition, in this study, we investigated the dependent variables of cancer such as age, gender, and tumor grade, but we didn't observe any significant changes.

Despite a significant difference of miR-371 and miR-373 expression between tumor and nontumor samples, the data obtained from ROC analysis show a low sensitivity and specificity for these two miRNAs and as a result these miRNAs can't be a reliable tumor marker to diagnose and classify the esophageal cancer. But it seems that miR-372 (P = 0.02, sensitivity = 78%, and feature = 60%) is more capable of discriminating tumor and nontumor esophageal samples compared to other members of this cluster and need to be confirmed in further studies.

However, more study is needed on the expression and function of miR-371–373 cluster to assign its fundamental role in tumor progression and recurrence in ESCC.

Financial support and sponsorship

This study was financially supported by deputy of research, Golestan University of Medical Sciences (Grant Number: 35619112276).

Conflicts of interest

There are no conflicts of interest.



 
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