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ORIGINAL ARTICLE
Year : 2021  |  Volume : 17  |  Issue : 3  |  Page : 749-755

Detection significance of miR-3662, miR-146a, and miR-1290 in serum exosomes of breast cancer patients


1 Department of Clinical Laboratory, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China
2 Department of Molecular Diagnosis Center, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Peking University Cancer Hospital and Institute, Beijing, China
3 Department of Breast Surgery, Beijing Chao-Yang Hospital, Capital Medical University, Beijing, China

Date of Submission24-Jan-2021
Date of Decision19-Feb-2021
Date of Acceptance18-Apr-2021
Date of Web Publication9-Jul-2021

Correspondence Address:
Sha Li
Department of Clinical Laboratory, Beijing Chao-Yang Hospital, Capital Medical University, Beijing 100020
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.jcrt_280_21

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 > Abstract 


Context: The potential relationship between exosomal microRNAs (miRNAs) and clinical symptoms in breast cancer patients and the expression levels of exosomal miRNAs in patients undergoing surgery and chemotherapy are still unclear.
Aims: The aim of this study was to explore the correlation among exosomal miRNAs and clinical features and treatment in breast cancer patients.
Materials and Methods: First, exosomes were isolated from the serum of patients with breast cancer and healthy controls. Next, the features of exosomes were identified by transmission electron microscopy, nanoparticle tracking analysis, and Western blot assays. Then, we detected the expression of the top-ranked miRNAs (miR-3662, miR-16-1, miR-146a, miR-1290, and miR-29c) in sixty breast cancer patients and twenty healthy controls using quantitative real-time polymerase chain reaction.
Statistical Analysis Used: The differential expression was measured by the Mann–Whitney U-test.
Results: The relative expression of miR-3662, miR-146a, and miR-1290 in serum exosomes was significantly higher in patients than healthy controls. Moreover, significant differences were found in the lymph node metastasis and clinical stage of breast cancer as the miRNA levels changed, but their expression levels in exosomes and sera were not correlated. In addition, exosomal miR-3662, miR-146a, and miR-1290 were shown to be valuable biomarkers to monitor patient condition in the course of surgery and chemotherapy.
Conclusions: Exosomal miR-3662, miR-146a, and miR-1290 may have promising predictive value and could be utilized as biomarkers for diagnosis and preventative strategy development.

Keywords: Breast cancer, chemotherapy, exosomes, microRNAs, tumor marker


How to cite this article:
Li S, Zhang M, Xu F, Wang Y, Leng D. Detection significance of miR-3662, miR-146a, and miR-1290 in serum exosomes of breast cancer patients. J Can Res Ther 2021;17:749-55

How to cite this URL:
Li S, Zhang M, Xu F, Wang Y, Leng D. Detection significance of miR-3662, miR-146a, and miR-1290 in serum exosomes of breast cancer patients. J Can Res Ther [serial online] 2021 [cited 2021 Jul 29];17:749-55. Available from: https://www.cancerjournal.net/text.asp?2021/17/3/749/321029




 > Introduction Top


Breast cancer is one of the most frequent female malignant tumors, and its incidence has been increasing year by year.[1] The main cause of death resulting from breast cancer is recurrence or metastasis.[2] Therefore, the identification and detection of key genes that determine progression and metastasis are urgently needed for diagnosis and molecular targeted therapies.

MicroRNAs (miRNAs) are a kind of noncoding, single-stranded RNA consisting of 19–24 nucleotides that inactivate genes by degrading target mRNAs or inhibiting the translation of specific proteins.[3] Aberrantly expressed miRNAs may play an important role as either tumor suppressors or promoters in a variety of carcinomas.[4] It has been reported that miRNAs are potential tumor markers to aid in the diagnosis and treatment of breast cancer;[5] for example, the expression of miRNA-200c was lower in the triple-negative (TN) breast cancer group than in the ER+/PR+group.[6]

Exosomes, which are small vesicles with lipid bilayers, approximately 30–150 nm in diameter, are widely present in various bodily fluids, including sera, saliva, and urine. Current studies have found that exosomes are rich in nucleic acids (mRNAs, miRNAs, lncRNAs, and circRNAs), proteins, and cholesterol. Exosomal miRNAs are relatively stable because the vesicle structure enclosing the miRNAs prevents RNase degradation.[7],[8] Exosomal miRNAs can affect the physiological state of cells and are closely related to the occurrence and progression of a variety of diseases, including breast cancer.[9],[10] The predictive value of breast cancer exosomal miRNAs has also become a research focus.

Interestingly, the top-ranked miRNAs (miR-3662, miR-16-1, miR-146a, miR-1290, and miR-29c) encapsulated by exosomes were differentially expressed in MDA-MB-231, MCF-7, and MCF-10A cells, showing differential expression profiles of exosomal miRNAs in breast cancer cells compared to normal epithelial cells.[11] However, whether these exosomal miRNAs may potentially be used as predictive biomarkers in breast carcinoma remains unknown.

In this study, we assessed whether these miRNAs exist in serum exosomes and are differentially expressed in exosomes of patients with breast cancer and healthy controls. In addition, we analyzed their correlation with clinical characteristics. Moreover, we identified exosomal miRNAs that may be used as biomarkers to monitor patients who received either surgery or chemotherapy treatment for breast cancer.


 > Materials and Methods Top


Patient samples

Blood samples were collected from sixty patients diagnosed with Stage I–III breast cancer who underwent surgery and twenty healthy controls at Beijing Chao-Yang Hospital between August 2018 and July 2019. None of the patients received chemotherapy, immunotherapy, or radiotherapy before surgery. This study was approved by the Ethics Committee of Beijing Chao-Yang Hospital.

To evaluate the effect of treatment on exosomal miRNAs in patients with breast cancer, we collected serum samples from the same patients before and after surgery and chemotherapy. The patients in the chemotherapy group received two chemotherapy cycles after surgery at Beijing Chao-Yang Hospital.

Serum preparation

Peripheral blood (2 mL) collected from patients and healthy controls was immediately used for the experiment or stored at 4°C for no more than 1 h. Samples were centrifuged at 3000 × g for 10 min, then at 10,000 × g and 4°C for 15 min, and finally stored at −80°C until use.

Exosome isolation and exosomal miRNA extraction

The exosomes were separated from the sera using Exosome Isolation Reagent (RiboBio, Guangzhou, China). The exosome samples were extracted by a HiPure Serum miRNA Kit (Magen, Guangzhou, China). RNA extraction was performed strictly based on the protocol.

Transmission electron microscopy

Isolated exosomes diluted in phosphate-buffered saline (PBS) were deposited onto carbon-coated Cu grids and allowed to absorb for 1 min. Then, 15 μL of 2.0% uranyl acetate was used to dye the grids for 1 min, after which the grids were dried for 15 min. Subsequently, transmission electron microscopy (TEM) was used to identify the morphology of the exosomes.

Nanoparticle tracking analysis

The exosomes were resuspended in PBS, and the size distribution and concentration of the isolated exosomes were observed using nanoparticle tracking analysis (NTA) with ZetaView PMX 110 (Particle Metrix, Meerbusch, Germany). Subsequently, NTA measurements were recorded and analyzed.

Western blotting assay

The isolated exosomes were incubated with radioimmunoprecipitation assay lysis buffer. The blots were incubated with antibodies against TSG101 and CD63 (dilution 1:1000, Abcam, UK).

MicroRNA detection by quantitative real-time polymerase chain reaction

Total RNA extracted from serum exosomes was reverse transcribed to cDNA. Briefly, quantitative real-time polymerase chain reaction (qRT-PCR) analysis was carried out with the miDETECT A Track miRNA qRT-PCR Starter Kit (Cat. No. C10712-1, RiboBio) according to the manufacturer's instructions. The assays were performed in triplicate, and the relative expression was measured by the 2ΔΔCt method. The primers for the polyA reaction were designed commercially (RiboBio, China).

Statistical analysis

SPSS 19.0 software (SPSS Inc., Chicago, IL, USA) was used to perform all statistical analyses, and P < 0.05 was considered statistically significant. Statistical data with a normal distribution are presented as the mean ± standard deviation, and differential expression was measured by the Mann–Whitney U-test.


 > Results Top


Characterization of purified serum exosomes

To determine whether miR-3662, miR-16-1, miR-146a, miR-1290, and miR-29c are secreted by exosomes, we first separated exosomes from the sera. Next, we characterized the exosomes through their morphology and size distribution using TEM and NTA. The isolated exosomes were round-shaped vesicles [Figure 1]a that had a mean size of 121.84 nm [Figure 1]b. Western blot assays were used to examine the expression of TSG101 and CD63, which are exosomal protein markers, and the results indicated that they were present in exosomes, but these markers were not found in the exosome-depleted supernatant [Figure 1]c.
Figure 1: Identification of serum exosomes. (a) Exosomes from breast cancer patient serum were verified by transmission electron microscopy (scale bars, 200 nm and 100 nm). (b) The size distribution of exosomes from the sera of breast cancer patients is based on nanoparticle tracking analysis data. (c) The exosomal markers were identified using Western blotting

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Expression of microRNAs

Analysis of the expression of miRNAs in sixty breast cancer patients and twenty healthy controls showed that the expression levels of exosomal miR-3662, miR-146a, and miR-1290 were significantly increased in breast cancer patients compared to healthy controls (P = 0.004, P = 0.002, and P = 0.002, respectively), whereas exosomal miR-16-1 and miR-29c expression did not significantly differ between the two groups [Figure 2]. In addition, the expression level of serum miR-146a was higher in breast cancer patients than in healthy controls, but no significant changes in the expression of serum miR-3662 and miR-1290 were found between the two groups [Figure 2]. Correlation analysis showed no significant correlations in the expression of miR-3662, miR-146a, and miR-1290 in the exosomes and sera (P = 0.430, P = 0.352, and P = 0.780, respectively) [Table 1].
Figure 2: Serum and exosomal microRNAs extracted from breast cancer patients and healthy controls. The exosomal miR-3662 (a), miR-146a (c), and miR-1290 (d) expression levels were more elevated in breast cancer patients than in healthy controls, while no clear differences were found in the expression of exosomal miR-16-1 (b) and miR-29c (e) between the two groups. The values are expressed as the means ± standard deviation. **P < 0.01

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Table 1: Correlations between exosomal and serum microRNA expression levels

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The correlation between exosomal microRNA expression and different clinical characteristics of breast cancer

In the analysis of exosomal miRNA expression and its relationship with clinicopathological features, there was no difference in age, menopausal status, intravascular tumor thrombus, or estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (HER2) status [Table 2]. Exosomal miR-3662 expression was elevated in well-differentiated and moderately differentiated breast carcinoma compared with poorly differentiated carcinoma. A high level of exosomal miR-146a was found in patients with tumor sizes >2 cm. The exosomal miR-3662, miR-146a, and miR-1290 levels were higher in patients with lymph node metastasis than in those without lymph node metastasis [Figure 3]a. Exosomal miR-3662, miR-146a, and miR-1290 expression in patients with Stage I disease was significantly lower than that in patients with Stage II/III disease [Figure 3]b. Taken together, our data further showed that increased miRNA expression in exosomes could be relevant to the progression of breast cancer.
Figure 3: Comparisons of exosomal microRNA expression levels with clinicopathological features. The exosomal microRNA expression stratified by (a) lymph node metastasis and (b) tumor, node, and metastasis stage was evaluated. The expression levels of different microRNAs were calculated by quantitative real-time polymerase chain reaction. The values are expressed as the means ± standard deviation. *P < 0.05, ***P < 0.001

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Table 2: Correlations between exosomal microRNA expression and clinicopathological factors in breast cancer patients

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The effects of treatment on exosomal microRNA expression in breast cancer patients

Changes in exosomal microRNA expression before and after surgery

In this study, sixty patients were monitored to assess changes in exosomal miRNAs (miR-3662, miR-146a, and miR-1290) within a short time before and after surgery. The exosomal miRNA (miR-3662 and miR-146a) expression in the surgery group was significantly lower than that in the preoperative group [P < 0.001 and P < 0.001, [Figure 4]a].
Figure 4: Changes of exosomal microRNA expression levels with clinical treatment. (a) Changes in exosomal miR-3662, miR-146a, and miR-1290 levels before and after surgery. (b) Changes in the expression levels of exosomal miR-3662, miR-146a, and miR-1290 before and after chemotherapy. ***P < 0.001 by paired-samples t-test

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Changes in exosomal microRNA expression before and after chemotherapy

To test the possible utility of exosomal miRNAs (miR-3662, miR-146a, and miR-1290) as biomarkers for the prediction of chemotherapy efficacy, sixty patients in the chemotherapy group were selected to compare the levels of exosomal miRNAs before and after chemotherapy. The expression of miR-146a in exosomes decreased sharply after chemotherapy compared to that before chemotherapy [P < 0.001, [Figure 4]b].


 > Discussion Top


The development of breast cancer is a complex process involving abnormal expression of various genes, abnormal molecular structure, and abnormal interactions between cancer cells and the microenvironment, which is pivotal to promote progression. Exosomes, membrane-derived vesicles that are regarded as important mediators of intercellular communication, carry lipids, proteins, mRNAs, and miRNAs and may be transferred to recipient cells through target cell membranes. In our study, differentially expressed exosomal miRNAs were detected in the serum of patients and healthy controls. In addition, serum exosomal miRNA expression was correlated with clinicopathological factors of breast cancer and used to monitor breast cancer patients who received either surgery or chemotherapy treatment during the course of the disease.

At present, exosomes are commonly isolated from sera using the chemical precipitation method.[12],[13] Based on this method, exosomes were successfully extracted from the sera of breast cancer patients and healthy controls.

Exosomes are small cell-derived vesicles that are selectively released from some membrane-associated substances and multivesicular bodies. Exosomes usually feature a round shape and a size range of ~40 to 160 nm in diameter and are characterized by the surface expression of specific protein markers such as CD63, CD81, and TSG101.[14],[15] Our findings are similar to the above studies, as we observed the characteristic round shape by TEM and size (121.84 nm) by NTA. Moreover, the expression of CD63 and TSG101 in the vesicular samples was also detected. Thus, these data demonstrate that the bodies we separated from the sera of breast cancer patients and healthy controls correspond to exosomes.

Exosomes can carry and transport various molecular constituents, including mRNAs, miRNAs, proteins, and lipids.[16] Exosomes promote cell-to-cell communication and influence the physiological and pathological development of diseases; thus, as molecular constituents of exosomes, miRNAs have been used to represent different health conditions, indicating that they may be important noninvasive biomarkers for diseases such as cancers.[17],[18] In the present study, exosomal miR-3662, miR-146a, and miR-1290 expression in breast cancer patients was markedly higher than that in healthy controls.

Differential expression profiles of additional miRNAs in breast cancer patients and healthy controls have been elucidated by many studies, but how these molecules play a role in breast cancer needs to be explored. Powrózek et al.[19] found that miR-3662 was upregulated in patients with lung cancer compared to healthy controls, and the high expression level of miR-3662 was associated with a higher stage of lung cancer; therefore, miR-3662 could be a potential early lung cancer biomarker. Previous studies have indicated that miR-146a promotes the proliferation and invasion of breast cancer, and miR-146a is more highly expressed in TN breast carcinoma than in non-TN breast carcinoma.[20],[21] The expression of miR-1290 was higher in Stage I, II, and III breast cancer patients than in Stage IV breast cancer patients; therefore, miR-1290 could potentially be utilized for the early detection of breast cancer. In addition, miR-1290 expression was slightly lower in patients with the luminal subtype than in patients with the HER2 and TN subtypes.[22]

In the present study, the increased expression of miR-3662, miR-146a, and miR-1290 in the serum exosomes of breast cancer patients implies that these miRNAs may be key genes affecting the physiopathological process of breast cancer. Furthermore, we found that increased miR-3662, miR-146a, and miR-1290 expression levels in exosomes were strongly correlated with advanced clinical stages and lymph node metastasis.

miRNA expression in the sera and exosomes manifests different aspects of microenvironmental changes in vivo. Due to the lack of a distinct relationship between serum miRNA and exosomal miRNA expression in our data, these two kinds of experiments cannot be substituted for each other. In addition, miRNAs in the serum may be unstable because of the presence of RNase, while the vesicular nature of exosomes may protect RNA from degradation.[23],[24] Therefore, exosomal miRNAs could be suitable as biomarkers in breast tumors.

Our findings indicated that the expression levels of miR-3662 and miR-146a were lower after surgery than before surgery. The reason could be that radical resection led to a sharp decrease in the miRNA levels over time.

Yasui et al.[25] reported that cell proliferation was inhibited by miR-3662 knockdown and that the expression of miR-3662 was correlated with antiviral drug resistance in adult T-cell leukemia/lymphoma cell lines. The most upregulated miRNAs in MCF-7/cis-diamminedichloroplatinum cells were miR-146a, miR-10a, and miR-221/222.[26] Ye et al.[27] found that miR-1290 was overexpressed in all 5-FU-resistant variants in a panel of colon cancer cell lines and reduced the sensitivity to 5-FU in vitro; however, the correlation between exosomal miRNAs and chemotherapy in breast cancer patients has yet to be reported. In the current study, we report that exosomal miR-146a expression was much lower after chemotherapy than before chemotherapy.

Our results indicate that expression level changes in exosomal miRNAs (miR-3662, miR-146a, and miR-1290) may play a vital role in the progression of breast cancer. The number of participants involved in our study is limited, so in future research, we need to increase the sample size and add cell experiments on signaling pathways and confirm the role of these miRNAs as effective biomarkers for disease prediction in breast cancer patients.


 > Conclusions Top


This study indicated that the high expression levels of miR-3662, miR-146a and miR-1290 in the exosomes of breast cancer patients were associated with the lymph node metastasis and stage of breast cancer. In addition, exosomal miR-3662, miR-146a and miR-1290 may be promising biomarkers to clinically monitor patients' course of surgery and chemotherapy.

Ethics approval

All procedures involving human participants were approved by the Beijing Chao-Yang Hospital Ethics Committee, which waived the requirement for informed consent from participants enrolled in this study.

Financial support and sponsorship

This study was financially supported by the Beijing Natural Science Foundation (grant no. 7214235) and the Beijing Municipal Administration of Hospitals Clinical Medicine Development of Special Funding Support (code: ZYLX201811) .

Conflicts of interest

There are no conflicts of interest.



 
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