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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 15  |  Issue : 5  |  Page : 1092-1097

Circulating miR-21 and miR-155 as potential noninvasive biomarkers in Iranian Azeri patients with breast carcinoma


1 Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
2 Department of Thorax Surgery, Noor Nejat Hospital, Tabriz, Iran

Date of Web Publication4-Oct-2019

Correspondence Address:
Esmaeil Babaei
Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz, Iran
Iran
Mohammad-Ali Hosseinpour-Feizi
Department of Animal Biology, Faculty of Natural Sciences, University of Tabriz, Tabriz
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_1227_16

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 > Abstract 


Background: Breast cancer (BC) is the most common cause of cancer-related mortality among women. Despite recent advances in diagnosis and prognosis of breast carcinomas, noninvasive biomarkers have been poorly identified. We evaluated the biomarker potential of miR-21 and miR-155 in tissue and plasma specimens of Iranian Azeri patients.
Materials and Methods: Tumor specimens, paired nontumoral adjacent tissues, and matched plasma samples were collected from a number of thirty Iranian Azeri women with breast carcinoma. Plasma of healthy women was used as the control. The relative expression of miR-21 and miR-155 was measured by real-time polymerase chain reaction.
Results: Our data revealed that the expression levels of miR-21 and miR-155 in tumor tissues are significantly higher than paired nontumoral adjacent specimens (P < 0.05). Furthermore, receiver operating characteristic (ROC) curve analysis of samples showed the area under the ROC curve of 0.81 for miR-21 and area of 0.83 for miR-155. In addition, statistical analysis showed that miR-21 and miR-155 RNAs are significantly detected in the plasma of BC patients compared to healthy specimens (P < 0.05). Circulating miRNAs yielded area under the ROC curve of 0.99 for miR-21 and 0.92 for miR-155.
Conclusion: Our data showed that miR-21 and miR-155 oncomiRs can be considered as noninvasive biomarkers for monitoring breast carcinomas. However, further investigations are needed to confirm the use of these noncoding RNAs in pathology.

Keywords: Biomarkers, breast, early detection of cancer, microRNAs, prognosis


How to cite this article:
Soleimanpour E, Babaei E, Hosseinpour-Feizi MA, Montazeri V. Circulating miR-21 and miR-155 as potential noninvasive biomarkers in Iranian Azeri patients with breast carcinoma. J Can Res Ther 2019;15:1092-7

How to cite this URL:
Soleimanpour E, Babaei E, Hosseinpour-Feizi MA, Montazeri V. Circulating miR-21 and miR-155 as potential noninvasive biomarkers in Iranian Azeri patients with breast carcinoma. J Can Res Ther [serial online] 2019 [cited 2019 Oct 20];15:1092-7. Available from: http://www.cancerjournal.net/text.asp?2019/15/5/1092/243476




 > Introduction Top


Breast cancer (BC) is one of the most common cancers among women, especially in industrial countries.[1] Screening for BC allows early detection of malignancy which leads to reduce the mortality rate. Although various imaging techniques are used for screening of breast lesions, their sensitivity and specificity are debatable. Therefore, developing a suitable, reliable, cost-effective, accurate, and noninvasive screening method for cancer diagnosis is required. MicroRNAs (miRNAs/miRs) are endogenous and short single-strand RNA molecules (20–23 nucleotides) that regulate gene and protein expression through targeting messenger RNAs (mRNAs). These small non-coding RNAs can degrade, destabilize, or inhibit translation of mRNA by binding to 3'-UTR of target mRNA.[2],[3] Circulating miRNAs, molecules that shift to body fluids, are potential to use as cancer biomarker due to their high stability, availability, and their capacity to reflect the tumor status.[4]

According to previous studies, miRNA deregulations were associated with several diseases such as cancer,[5] neurodegenerative disease,[6] diabetes mellitus,[7] cardiovascular diseases,[8] psychiatric disease,[9] immune responses,[10] kidney and liver diseases,[11],[12] infertility,[13],[14] and also aging.[15]

Although recent advances in early diagnosis and treatment have been very impressive, scientists are still faced with some challenges regarding the diagnosis and treatment of cancer. On the other hand, the use of some specific and noninvasive biomarkers for early detection and prognosis has raised hopes for dealing with tumor malignancies and applying appropriate treatment.

Recent works showed that miR-21 and miR-155 can be considered as most significant altered miRNAs in the majority of BCs.[16],[17],[18] On the other hand, Zhao et al. had reported that the expression profiling of circulating miRNAs is ethnic dependent.[19] Thus, the aim of the study was to assess the expression pattern of miR-21 and miR-155 in plasma of BC patients living in North West of Iran and then evaluate the diagnostic potential of these miRNAs. To do this, all specimens were collected from an ethnic group (Iranian Azeri) living in North West of Iran. In comparison with nontumoral groups, our results revealed that the levels of miR-21and miR-155 were significantly higher in both tissue and plasma.


 > Materials and Methods Top


This study was approved by the Clinical Research Ethics Committee of Noor-Nejat Hospital, Tabriz, Iran. Informed written consent was obtained for each patient and healthy volunteers. The clinical data were prospectively collected for all the participants involved.

Tumor tissues, paired nontumoral adjacent specimens, and matched plasma samples were collected from thirty Iranian Azeri women with breast carcinoma with newly diagnosed breast carcinomas. Pathological analysis was used to confirm the histology, and the patients were staged according to the tumor-node-metastasis staging system of the International Union Against Cancer. According to the pathological results, the type of all tissue samples was invasive ductal carcinoma (IDC).

In the control group, 25 blood samples were collected from healthy Iranian Azeri women who had previously been diagnosed without any type of malignancy or other related benign diseases. In addition, they did not have any cancerous patient in their first and second families. Control women were matched to the BC patients according to the age, place of birth, and lifestyle.

Sample preparation and total RNA isolation

For miRNA extraction, blood samples from all patients and control groups were collected in ethylenediaminetetraacetic acid tubes and followed by plasma isolation. Briefly, blood samples were centrifuged at 1500 g for 10 min to spin down the blood cells, and the supernatants were transferred into other tubes, followed by a second centrifugation at 3000 g for 5 min. Finally, a third centrifugation was performed at 4000 g for 5 min. The supernatant, including plasma, was transferred to RNase/DNase-free tubes and stored at −80°C till use. The fresh tumors and paired marginal tissues were obtained after surgical resection and immediately transferred to an RNse/DNase-free Eppendorf tube and stored in liquid nitrogen until use.

Total RNA was extracted from 100 mg of tissue specimens and 1 ml of plasma samples using TRIzol ® reagent (Invitrogen, Life Technologies, USA) according to the manufacturer's instructions. The quality and quantity of RNAs were determined using NanoDrop 100 Spectrophotometer (Thermo Scientific Wilmington, DE, USA).

Quantitative real-time polymerase chain reaction

After RNA preparation, the first-strand cDNA was synthesized using PrimeScript RT Reagent Kit (Parsgenome MiR-Amp, Iran), according to the manufacturer's instructions. The expression of miR-21 and miR-155 was quantified by quantitative real-time polymerase chain reaction (qRT-PCR) wherein 5s-rRNA was used as internal control. The qRT-PCR was carried out using a SYBR Premix Ex Taq Kit (Takara, Japan) on Rotor-gene instrument (Qiagen, Germany). Each sample was run in triplicate for analysis. The amplification specificity was validated by melting curve analysis and agarose gel electrophoreses.

Statistical analysis

Expression profiles taken by real-time PCR were analyzed using the 2− ΔΔ Ct method. Biomarker potential of miR-21 and miR-155 was also evaluated by receiver operating characteristic (ROC) analysis. Statistical analysis was performed using SPSS version 16.0 software; P ≤ 0.05 was considered statistically significant. Moreover, t-test and one-way ANOVA have been used for studying the association between miR-21 and miR-155 expression and clinicopathological parameters.


 > Results Top


No significant differences were observed between the BC patients and controls in the distribution of age, gender, and the place of living. Clinicopathological reports of all participants are summarized in [Table 1].
Table 1: Clinic-pathological features of breast cancer patients

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Expression pattern of microRNAs in tissue samples of breast cancer and nontumoral adjacent tissues

In the present study, we examined the expression of miR-21 and miR-155 in BC tissues and paired nontumoral adjacent tissues (NATs). miR-21 and miR-155 showed the same patterns of overexpression. As shown in [Figure 1]a and [Figure 1]b, their expression levels were significantly different and elevated in BC tissue compared to NATs (miR-21: P = 0.00 and miR-155: P = 0.00).
Figure 1: Relative expression of miR-21 and miR155 in tissue and plasma. (a) Overexpression of miR-21 in tissue samples. (b) miR-155 in tissue samples. (c) miR-21 in plasma samples. (d) miR-155 in plasma samples of patients in comparison with nontumoral adjacent tissues and healthy controls

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MicroRNA expression in the plasma samples of breast cancer and healthy control

Circulating miR-21 and miR-155 of BC patients and healthy controls (HCs) consistent with tissue samples showed similar patterns of overexpression in cancerous specimens compared to the healthy group (miR-21: P = 0.02 and miR-155: P = 0.01) [Figure 1]c and [Figure 1]d.

The relationship between miR-21 and miR-155 expression between breast cancer tissues and paired plasma samples

Pearson–Rho test was carried out to compare the relative expression of miR-21 and miR-155 in BC tissues and their paired plasma samples. The results showed r = 0.52 and r = 0.60 for miR-21 and miR-155, respectively (P < 0.01), that pretend a significant direct mode of correlation between miR expression profile in tissues and plasmas of BC.

Relationship between miR-21 and miR-155 expressions and clinicohistopathological features

There is no significant correlation between miR-21 and tumor size (P = 0.23), lymph nodes (P = 0.315), tumor stages (P = 0.4), and age (P = 0.06). There is also no correlation between miR-155 and tumor size (P = 0.82), lymph nodes (P = 0.329), tumor stages (P = 0.396), and age (P = 0.059).

Receiver operating characteristic curve analysis

The capability of miR-21 and miR-155 to function as a BC tumor marker was measured by ROC curve analysis. The area under the curve (AUC) was calculated to evaluate the specificity and sensitivity of predicting BC and nontumoral tissue as well as plasma by miR-21 and miR-155 expression levels. Based on the analysis of ROC curve, miR-21 showed a ROC area of 0.81 in tissue and 0.99 in plasma. ROC area for miR-155 was 0.83 for tissues and 0.92 for plasma samples [Figure 2]a and [Figure 2]b.
Figure 2: (a) Receiver operating characteristic curve analysis of miR-21 and miR-155 in tissue samples was plotted for discriminating breast cancer from normal controls. (b) Receiver operating characteristic curve analysis of miR-21 and miR-155 in plasma samples was plotted for discriminating breast cancer from normal controls

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 > Discussion Top


According to the WHO reports, BC is the first cause of cancer mortality among Iranian women.[20]

A general research on BC study in Iranian population has shown that the mean age of BC patients is 49 years. Meanwhile, the incident age of the BC is approximately one decade earlier than western countries. However, certain genetic factors can put some younger women at a high risk of cancer. Furthermore, IDC is the most common type of cancer among both genders,[21],[22] and 5-year survival rate of BC in Iran was varied between 62.1% and 76.2% that is related to several factors such as family history, geographical region, lifestyle, knowledge, and attitude.[22]

Nowadays, digital mammography, ultrasonography, magnetic resonance imaging, and nuclear medicine are common imaging techniques that are used to screen and identify breast lesions, but their specificity and sensitivity are debating.[23] Gene expression patterns have been examined to develop more accurate predictive and prognostic biomarkers that can be affordably used as early detection.

miRNAs, small and highly conserved non-coding RNA, are key regulators that control cell development, cell proliferation, apoptotic process, and response to different external and stress signals.[24] MicroRNAs are endogenous and single-stranded RNA molecules (20–23 - nucleotide) that show diverse and specific expression patterns in different tissues and diseases such as cancer.[2] They are strongly conserved among invertebrates, vertebrates, and plants,[25] and currently, more than 2500 miRNAs have been identified in human (miRbase version 20).[26] MiRNAs suppress the mRNA expression and/or inhibit translation through binding predominantly to the 3'-UTR of target mRNA.[2] However, miRNAs can also target the 5'-UTRs.[27] The significant point of miRNA is that a single miRNA can target hundreds of mRNAs that lead to disruption of expression of several mRNAs and proteins;[28] they also could act as oncogenes (oncomiR) or tumor suppressors (Ts-mir).[2]

Lawrie et al. for the first time measured the miRNA levels in serum of patients with diffuse large B-cell lymphoma.[29] In addition to the serum and plasma, circulating miRNAs are detectable in several body fluids such as tears, breast milk, bronchial lavage, colostrum and seminal, amniotic, pleural, peritoneal, and cerebrospinal fluids.[30] Recent studies illustrated the potential use of circulating biomarker in different types of cancer, such as tongue,[31] colorectal cancer,[32] ovarian cancer,[33] BC,[19],[34] renal cell carcinoma,[35] and glioblastoma.[36] Circulating miRNAs are strikingly stable in high level of RNase activity and even under severe conditions such as boiling, different pH levels, and multiple freeze–thaw cycles.[37],[38] Hypothetically, this stability is due to the fact that miRNAs are covered with microparticles such as exosomes or bound to Ago2 protein – a part of the RNA-induced silencing complex.[39],[40] In this study, we evaluated the expression of miR-21 and miR-155, as two proved miRs with significant role in cancer initiation and/or progression.

Briefly, studies revealed miR-21 as a key oncomR, since it upregulates in a wide range of human tumors and cancer cell lines, including glioblastoma, head and neck cancer, ovarian cancer, B-cell lymphoma, hepatocellular carcinoma, cervical cancer, colorectal, and lung cancer and BC.[41],[42],[43],[44] The functional study reported the relationship between mir-21 expression and proliferation, cell growth, invasion, apoptosis, and metastasis.[45],[46],[47],[48] Si et al. studied the expression of 10 miRs on 48 tissue and 100 serum samples of patients and reported that the level of miR-21 was significantly higher in tissue and serum samples of BC compared to their normal counterpart.[49] Kumar et al. also reported the overexpression of circulating miR-21 in BC patients in comparison with HC.[50] Consistent with the previous studies, in this research, miR-21 was significantly upregulated in tissues and plasmas. As illustrated by the ROC curve [Figure 2]a and [Figure 2]b, AUC value was 0.81 for tissue samples and 0.99 for plasma samples of BC. All of these findings suggested that circulating miR-21 has potential use as noninvasive BC biomarker.

Moreover, miR-155 is known to regulate multiple aspects of BC progression such as cell growth and survival, cell migration and invasion, cell adhesion junction, apoptosis proliferation, and also drug resistant. Furthermore, the upregulation of miR-155 is correlated with hormone receptor status of breast cancer patients.[51],[52],[53],[54] Iorio et al. reported overexpression of miR-21 and miR-155 in 76 BC samples.[55] Furthermore, Liu et al. evaluated the expression of miR-155 in serum samples of 20 BC patients and 10 healthy controls and showed that miR-155 was upregulated in tumor samples.[56] In accordance with the previous findings, the overexpression of miR-155 in tissue and plasma samples as well as ROC curve analysis with AUC value of 0.83 for tissue and 0.92 for plasma samples showed the potential usefulness of circulating miR-155 for the detection of BC as a noninvasive manner.

The Pearson–Rho test was performed to determine the correlation of miRNA expression pattern in tissue and paired plasma counterparts. miR-21 and miR-155 showed r = 0.52 and r = 0.60, respectively, which revealed that characteristic expression patterns of plasma could reflect the characteristic of the tissue expression pattern. On the other hand, the origin of circulation miRNAs that we measured is breast tissue.


 > Conclusion Top


These findings suggest that circulating miR-21 and miR-155 expression quantification may be used to discriminate the BC patients from HC in Iranian Azeri women population. As, for accessing plasma samples, there is no need to biopsy or surgery, using circulating miRs can be a noninvasive alternative for BC detection, especially in the early stage of BC. Furthermore, it might be used as a screening biomarker, particularly for women who have BC in their family.

Acknowledgment

This work has been done at the University of Tabriz. The current study has also been supported by the Center for International Scientific Studies and Collaboration, Tehran, Iran.

Financial support and sponsorship

The current study has been supported by the Center for International Scientific Studies and Collaboration, Tehran, Iran.

Conflicts of interest

There are no conflicts of interest.



 
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