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Table of Contents
Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 64-70

Circulating miR-210 and miR-23b in bladder Cancer

1 Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Urology, Faculty of Medicine, Cairo University, Cairo, Egypt

Date of Submission30-Jul-2020
Date of Decision25-Nov-2020
Date of Acceptance22-Dec-2020
Date of Web Publication22-Jun-2021

Correspondence Address:
Mona Fathy
Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/UROS.UROS_112_20

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Purpose: This study is aimed to assess the serum expression levels of miR-210 and microRNA-23b (miR-23b) in bladder cancer (BC) patients to evaluate their potential as noninvasive biomarkers. Materials and Methods: This study included 93 subjects divided into the following three groups: Group Ia, 31 patients newly diagnosed with BC; Group Ib, Group Ia patients 6 months after medical and/or surgical treatment; and Group II, 31 healthy controls. The gene expressions of miR-210 and miR-23b were determined using quantitative SYBR Green reverse transcription real-time polymerase chain reaction. Results: The expression of miR-210 was significantly higher in BC patients compared to the controls (P = 0.012), while miR-23b did not show any difference. miR-210 expression in BC patients did not differ before and after treatment (P = 0.89). Area under the curve of the receiver operating characteristic analysis for miR-210 in distinguishing BC from controls was 0.686 (95% confidence interval, 0.553–0.818) with 71% sensitivity and 61% specificity. Conclusion: miR-210 can serve as a noninvasive diagnostic marker for BC; however, it cannot be used during treatment follow-up. miR-23b cannot be used as a diagnostic nor prognostic marker for BC.

How to cite this article:
Hany N, Bahgat A, Youssef O, Fayyad A, Kotb A, Al-Khatib S, Fathy M. Circulating miR-210 and miR-23b in bladder Cancer. Urol Sci 2021;32:64-70

How to cite this URL:
Hany N, Bahgat A, Youssef O, Fayyad A, Kotb A, Al-Khatib S, Fathy M. Circulating miR-210 and miR-23b in bladder Cancer. Urol Sci [serial online] 2021 [cited 2023 Feb 5];32:64-70. Available from: https://www.e-urol-sci.com/text.asp?2021/32/2/64/318994


  Clinical Significance Top

  • Micro RNA-210 gene expression levels can serve as a noninvasive diagnostic marker for bladder cancer
  • Micro RNA-23b gene expression levels cannot be used as a diagnostic nor prognostic serum marker for bladder cancer.

  Introduction Top

Bladder cancer (BC) represents the most common malignancy of the urinary tract worldwide, leading to significant morbidity and mortality.[1] At initial diagnosis, about 70% of BC patients have cancers confined to the epithelium or sub-epithelial connective tissue, termed nonmuscle-invasive BC (NMIBC). Unfortunately, more than 50% of these cancers recur and 15%–20% progress to a muscle-invasive form (MIBC) during follow-up.[2]

Major risk factors for BC include tobacco smoking, occupational exposure to urothelial carcinogens, cyclophosphamide intake, history of bilharziasis, recurrent calculi, and recurrent cystitis.[3] Cystoscopy-guided biopsy with histological evaluation has high diagnostic accuracy, but it is invasive, expensive, and inconvenient for general cancer screening. Therefore, new noninvasive diagnostic and prognostic markers and more effective treatment strategies are required. One approach to achieve these goals is through the analysis of RNA networks.[4]

MicroRNAs (miRNAs) are short RNA molecules that are 22 nucleotides long. They function as posttranscriptional regulators by binding to complementary sequences in the 3′UTR of their target mRNAs. This usually results in translational repression or mRNA degradation, leading to reduced levels of the encoded protein. However, they can also induce gene expression by binding to complementary promoter sequences, thus upregulating translation.[5] A large body of evidence suggests that miRNAs are deeply involved in cancer pathogenesis.[6] Highly expressed miRNAs in cancer tissues may function as oncogenes by repressing tumor suppressors; conversely, miRNAs expressed at low levels in cancer tissues can also function as tumor suppressors by negatively regulating oncogenes.[7]

MiR-210 has been identified as a hypoxiamir, i.e., a miRNA that is upregulated by hypoxia.[8] miR-210 is evolutionarily conserved and is induced by hypoxia-inducible factor 1 via direct binding to the hypoxia-responsive element on the promoter of miR-210.[9] miR-210 is upregulated in most solid tumors, including breast cancer,[10] osteosarcoma,[11] colorectal cancer,[12] renal cancer,[13] glioma,[14] and head and neck squamous cell carcinoma (SCC).[15] This high expression is presumably due to the hypoxic nature of many expanding tumors, as disordered angiogenesis causes the inadequate blood supply to the lesions.[16] Alterations in the expression levels of miR-210 have been associated with an advancing stage and grade of BC.[17]

MicroRNA-23b (miR-23b) has been implicated in cancer progression, metastasis, and cytoskeletal remodeling in several tumor types.[18] It was found to be downregulated in BC tissues compared to normal adjacent tissues, suggesting its potential diagnostic/prognostic role in predicting survival.[19]

Aim of the work

This study is aimed to assess the serum expression levels of miR-210 and miR-23b in BC patients to evaluate their potential as noninvasive biomarkers and explore their prognostic potentials.

  Subjects and Methods Top


In the current study, serum samples were collected from 31 de novo BC patients (Group Ia) with age ranging from 25 to 75 years, and from 31 healthy controls matched to sex and age (Group II). Their ages ranged from 27 to 70 years. Group Ib consists of the same 31 BC patients of Group Ia but 6 months after their medical and/or surgical treatment. All BC patients were recruited from the Urology Department of Cairo University. BC was confirmed via cystoscopy and biopsy. Regarding tumor pathology, 21 patients (96.8%) had transitional cell carcinoma and 10 (32%) had SCC. Regarding tumor staging, MIBC was recorded in 11 patients (35%), and 20 (65%) had NMIBC. This study was approved by the Ethical Committee of Cairo University Hospital (Approval number: N-69-2017). Informed consent was obtained from all the eligible patients.

Sample size calculation

MiRNA-210 was anticipated to be upregulated 2.75-fold in BC patients compared to controls according to Yang Y et al.(2015).[17] On the other hand, miR-23b was anticipated to be downregulated 0.6-fold in BC patients compared to controls according to Majid et al. (2013).[20] At a P = 0.05 and power of 80%, a total of 31 individuals were recruited in each group.

Method of detection of miR-210 and miR-23b expression levels

Serum samples and preparation of total RNA

Serum samples were stored at − 80°C until processing. RNA was isolated from the serum using the miRNeasy Mini Kit (Catalog no. 217004; QIAGEN GmbH, Hilden, Germany) according to the manufacturer's instructions. The RNA concentration was determined by measuring absorbance at 260 nm using the Quawell Q5000 UV-VIS SPECTROPHOTOMETER.

Reverse transcription

Complementary DNA (cDNA) was reverse-transcribed from the total RNA samples using the miScript MicroRNA Reverse Transcription (RT) Kit (Catalog no. 218161; QIAGEN GmbH). The RT master mix was prepared as follows: 4 μL of 5× miScript HiSpec Buffer, 2 μL of ×10 Nucleics Mix, and 2 μL of miScript RT Mix. Template RNA and RNase-free water were added to each tube containing the RT mix according to their RNA concentration to reach a final volume of 20 μL. The mixture was incubated at 37°C for 60 min, 95°C for 5 min, and then held at 4°C in a Biometra thermal cycler (Analytic Jena, Germany).

Real time polymerase chain reaction

After RT, the polymerase chain reaction (PCR) products were amplified from cDNA samples with the SYBR® Green PCR Kit (Catalog no. 218073; QIAGEN GmbH). Next, 5 μL cDNA product, along with 2 μL miScript specific primer Assay (forward primer), 2 μL miScript Universal Primer (reverse primer), and 1 μL RNase-free water were mixed with 12.5 μL QuantiTect SYBR Green PCR Master Mix. MiR-SNORD 68 was used for normalization (reference gene). The PCR conditions included an initial activation step at 95°C for 15 min, followed by 50 cycles of 94°C for 15 s, 55°C for 30 s, and 70°C for 30 s. The reactions were carried out in the StepOne real-time PCR system (Applied Biosystems, Foster City, CA, USA).

Data analysis: Comparative cycle threshold method

miRNA expression levels were measured using the cycle threshold (CT) method; the expression of each miRNA was calculated using the difference between its CT value and the average CT value of the reference gene per sample. The expressions of circulating miR-210 and miR-23b were normalized through relative fold change (2−ΔΔCT). MiR-SNORD 68 was used as the reference gene as it has high serum expression levels and was calculated relative to its expression in the serum of healthy controls. Relative expression (fold change) was then calculated using the equation 2-ΔΔCT.[21]

Statistical analysis

Data were encoded and entered using the statistical package Statistical Package for the Social Sciences (IBM SPSS, version 25.0, Armonk, NY: IBM Corp). Data were summarized using mean, standard deviation, median, minimum, and maximum for quantitative data and frequency (count) and relative frequency (percentage) for categorical data. Comparisons between quantitative variables were performed using the nonparametric Kruskal–Wallis, and Mann–Whitney U tests. For the comparison of serial measurements within each patient, the non-parametric Wilcoxon signed-rank test was used. For comparing categorical data, the Chi-square test was used. The Fisher's exact test was used instead when the expected frequency was <5. Correlations between quantitative variables were done using Spearman's correlation coefficient. The receiver operating characteristic (ROC) curve was constructed with an area under the curve (AUC) analysis performed to detect the best cutoff value of miRNA for the detection of cases and to calculate the sensitivity, specificity, and accuracy at different cutoff levels. P < 0.05 were considered statistically significant. The relative expression levels of miR-210 and miR-23b were characterized by their median and ranges. The associations of miR-210 and miR-23b with the patients' clinical-stage were analyzed with the Kruskal–Wallis test.

  Results Top

The demographic, clinical, and pathological data of the patients are summarized in [Table 1].
Table 1: Demoghraphic, clinico-pathological data characteristics of the studied groups

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Using miR-SNORD68 as a reference for miRNA, we determine that the miR-210 expression levels were significantly upregulated in the serum of BC patients before and after treatment (Groups Ia and Ib, respectively) compared to the controls (Group II; P = 0.012, P = 0.039), while there was no difference in the expression level of miR-210 among BC patients either before or after treatment [Groups Ia and Ib, P = 0.89; [Table 2] and [Figure 1].
Table 2: Median values of fold changes of studied miRNAs among different groups

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Figure 1: Median fold change of serum miR-210 expression level among the studied groups. The upper and lower limits of the boxes and the lines inside the boxes indicate the 75th and 25th percentiles and the median, respectively. The upper and lower horizontal bars denote the 90th and 10th percentiles, respectively. Small circles are out values. Extreme values are marked with a star

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Regarding the expression levels of miR-23b, there was no difference between BC patients before treatment (Group Ia) and the controls (Group II; P = 0.188). On the other hand, miR-23b was significantly upregulated in BC patients after receiving their treatment (Group Ib) compared to before receiving it [P = 0.031; [Table 2] and [Figure 2].
Figure 2: Median fold change of serum miR-23b expression level among the studied groups. The upper and lower limits of the boxes and the lines inside the boxes indicate the 75th and 25th percentiles and the median, respectively. The upper and lower horizontal bars denote the 90th and 10th percentiles, respectively. Small circles are out values. Extreme values are marked with a star

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Diagnostic performance of serum miR-210 and miR-23b for detection of bladder cancer

Since miR-210 expression levels were significantly upregulated among BC patients before receiving treatment (Group Ia) compared to healthy controls (Group II), ROC curve analysis was used to explore the potential utility of miR-210 expression levels as a diagnostic biomarker for BC. This ROC curve analysis demonstrated that the expression level of miR-210 can be a useful biomarker for distinguishing BC patients from healthy controls with an AUC of 0.686 (95% confidence interval, 0.553–0.818) [Figure 3]. At a cutoff value of 1.145 for miR-210 expression levels, the sensitivity, specificity, and diagnostic accuracy were 71%, 61%, and 66%, respectively.
Figure 3: Receiver operating characteristic curve analyses of miR-210 in group Ia versus Group II. area under the curve 0.686. The combination of miR-210 and miR-23b was tested as an miRNA panel to determine whether it has superior discrimination power over each miRNA alone using the receiver operating characteristic curve; the combination yielded no significant difference (data are not shown)

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All data are presented as median (min-max). Groups bearing the same initials are statistically insignificant from each other.

The median values of FC are shown relative to reference miR-SNORD68. Fold change formula = 2-ΔΔCT.

Concerning miR-210: Group Ia versus Group II: P = 0.012. Group Ib versus Group II: P = 0.039. Group Ia versus Group Ib: P = 0.89.

Concerning miR-23b: Group Ia versus Group II: P = 0.188. Group Ib versus Group II: P = 0.048. Group Ia versus Group Ib: P = 0.031.

Statistically significant difference at P < 0.05.

Correlation analysis between the studied miRNAs among bladder cancer patients

The expression levels of miR-210 and miR-23b showed a significant positive correlation among BC patients before (Group Ia: r = 0.372, P = 0.039) and after treatment (Group Ib: r = 0.504, P = 0.004).

Relationship between serum miRNA expression and clinical-pathological features

The relative expressions of serum miR-210 and miR-23b (normalized to miR-SNORD68) were assessed in relation to the clinical and pathological characteristics of the patients. The median value of fold change (relative expression) for serum miR-23b was significantly lower in hypertensive BC patients compared to normotensive patients (P = 0.046). Otherwise, no significant associations were found between the studied miRNAs and other clinical and pathological features [Table 3].
Table 3: Relationship between miR-210 and miR-23b expression levels and clinical-pathological features in bladder cancer patients

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  Discussion Top

The pathogenesis of BC has been extensively studied, with a focus on the molecular level and in particular on epigenetic factors. One of the most important epigenetic factors are miRNAs; it is one of the novel areas that are currently under study for cancer detection, prognosis, and therapeutic options.[12] Several factors make circulatory miRNAs a promising tool for noninvasive screening tests.[22] miRNAs are surprisingly stable in the blood despite the high activity of ribonucleases that can rapidly degrade RNA.[23] because they are protected from enzyme degradation, being packed in vesicles or bound to proteins/lipoproteins.[24] Moreover, <2 mL of blood is required and it can easily be transported in ice packs while preserving the miRNA content.[25] The differential expression of miRNAs in cancer patients also makes these molecules good candidates for biomarkers.

In this study, serum levels of miR-210 were significantly upregulated in BC patients compared to healthy controls (P = 0.012), while there was no significant difference in the expression levels of miR-23b between BC patients and controls (P = 0.188).

Hypoxia is a hallmark of the neoplastic microenvironment and a well-documented cause of therapeutic failure in clinical oncology.[26] Given the role of hypoxia in the induction of miR-210,[9] it is not surprising to find it upregulated in BC patients.

Studies have demonstrated that an elevated expression of miR-210 targets many biological cell functions, e.g. for example, it stimulates angiogenesis,[27] promotes cellular migration and invasion,[28] enhances double-stranded DNA breaks,[29] and possesses anti-apoptotic properties during cellular stress conditions.[27]

In line with this, several studies[17],[28] have found that miR-210 was significantly upregulated in BC patients. Furthermore, Liu et al.,[28] concluded that targeting cancer cells with synthetic anti-miR-210 inhibited the growth and migration and induced apoptosis of BC cells. In contrast, Yang et al.[29] found that miR-210 was downregulated in BC compared to normal tissues, and Zaravinos et al.[30] found no significant difference in miR-210 expression levels between normal and malignant bladder tissues. Although miR-210 promotes cell proliferation in many types of cancers, it has been also shown to have a tumor-suppressive role in a small number of cancers, including ovarian cancer,[31] esophageal SCC[32] and laryngeal SCC.[33] Thus, miR-210 can promote either tumor progression or suppression depending on the cell type. That is why we speculated that BC cell differentiation may affect miR-210 expression levels.

In the current study, the ROC analysis revealed the utility of serum miR-210 as a potential diagnostic marker for BC. At a cutoff value of 1.1457, the serum expression level of miR-210 showed a sensitivity of 71%, specificity of 61.3%, and diagnostic accuracy of 66.13% in differentiating BC from healthy controls, with an AUC of 0.686 (P = 0.012). These data show that miR-210 may serve to distinguish BC patients from healthy controls.

In this study, we found no significant difference in the expression levels of miR-210 among BC patients before and after treatment (P = 0.891), and could not find an association with the presence of metastasis or tumor recurrence. However, other studies found that increased miR-210 expression is associated with poor prognosis[29] and advancing stage and grade[17] in BC. On the other hand, Yang et al.[29] found that overexpression of miR-210 inhibited the proliferation, migration, and invasion of BC cells in vitro.

Several meta-analyses have demonstrated the ethnic differences in miRNA deregulations in cancer.[34],[35] Most studies on miRNAs as biomarkers were performed on Asian and European populations, with very few being performed on populations of African descent. Data from these studies showed differential expression of miRNAs between African-Americans and European-Americans in both breasts.[36] and lung cancer.[37] Owing to these ethnic differences, the clinical significance of miR-210 and its potential roles in BC remain unknown.

In the current study, the expression level of miR-210 was significantly upregulated in BC patients compared to controls; however, the miR-210 expression in BC patients was not different before and after treatment (P = 0.89) nor did it show significant differences with recurrence (P = 0.33) or metastases (P = 0.67). Similarly, Yang et al.[17] found that serum miR-210 was upregulated in patients with BC, and serum expression levels of miR-210 increased with advancing stage and grade. Moreover, serum miR-210 expression was found to be significantly reduced in postoperative samples and elevated in most patients with relapsed BC.

It remains unknown whether high circulating miR-210 levels can truly point to a diagnosis of BC, or if this is only a common phenomenon that manifests as a result of perturbations in the host immune response during the progression of any cancer as circulating miR-210 expression has also been described in other solid cancers, such as breast cancers,[10] kidney cancer,[38] and pancreatic cancer.[39]

We found no significant difference when comparing miR-23b expression levels between BC patients and controls (P = 0.188). miR-23b expression levels were higher in BC patients after treatment compared to before treatment (P = 0.031), yet no significant difference was observed regarding the presence or absence of tumor recurrence and metastasis. Thus, no diagnostic or prognostic role of miR-23b as a marker in BC could be found. Other studies[19],[20] found that miR-23b was downregulated in BC tissues compared to normal adjacent tissues, suggesting a potential diagnostic/prognostic role for miR-23b in discriminating malignant from normal tissues. Gottardo et al.[40] found that miR-23b was upregulated in BC tissues compared to normal bladder mucosa, which led them to speculate that miR-23b is an oncogenic miRNA.

  Conclusion Top

miR-210 can serve as a noninvasive diagnostic marker for BC, however, it cannot be used in treatment follow-up nor prognosis, whereas miR-23b cannot be used as a diagnostic nor prognostic marker for BC. Further wider-scale studies should be conducted on a larger number of patients to validate the significance of abnormal expression levels of miR-210 and miR-23b.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3]

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