Abstract
Circular RNAs (circRNAs) are a group of transcripts with enclosed configurations which can regulate gene expression. These transcripts have important roles in normal development and in the pathogenesis of disorders. Recent evidence has supported involvement of circRNAs in the development of bladder cancer. Several circRNAs such as circ_0058063, hsa-circRNA-403658, circPDSS1, circCASC15, circRNA-MYLK, and circRNA_103809 have been upregulated in bladder cancer samples. On the other hand, hsa_circ_0137606, BCRC-3, circFUT8, hsa_circ_001598, circSLC8A1, hsa_circ_0077837, hsa_circ_0004826, and circACVR2A are among downregulated circRNAs in bladder cancer. Numerous circRNAs have diagnostic or prognostic value in bladder cancer. In this review, we aim to outline the latest findings about the role of circRNAs in bladder cancer and introduce circRNAs for further investigations as therapeutic targets.
Introduction
Non-coding RNAs (ncRNAs) comprise several groups of RNA transcripts whose no protein is known to be encoded and thus considered as junk; however, they constitute a majority of expressed RNAs compared to protein-coding transcripts (). Circular RNAs (circRNAs) are a distinct class of ncRNAs in eukaryotic cells which have been identified via electron microscopy in 1979 for the first time (). Unlike coding-RNAs, circRNAs lack the 5′ cap and 3′ polyadenylated tail and do not mainly encode any protein; therefore, no primary function has been described for them (). However, peptide-coding circRNAs have also been recognized. Some findings have revealed developmental, pathogenic, and especially regulatory roles for circRNAs. As their name suggests, a close circular loop in circRNAs is formed by covalent linkages between the 5′ and 3′ ends of their transcripts. CircRNAs compared to their linear counterparts show higher stability against degrading agents like RNase R due to closed ends () but are found in lower quantities within the animal cells (), although higher abundance is reported for some circRNAs (). Their sequence is evolutionarily conserved, indicating selective pressure for them (). CircRNAs also show specific cell and tissue tendencies (). Their elevated levels in several diseases demonstrate their potentials as diagnostic biomarkers and also therapeutic potentials especially in cancers (). Today, due to development of advanced technologies like high-throughput RNA sequencing (RNA seq) and in situ experiments, a huge number of circRNAs have been recognized in animal cells (). Moreover, their regulatory roles in gene expression and pathogenesis of disorders have been recognized. Similar to other regulatory non-coding RNAs, regulatory functions of circRNAs are suggested to be exerted through modulating gene expression at different levels. Based on the gene region, circRNAs can be divided into three types: those originating from exons (exonic circRNAs), introns (intronic circRNAs), or exon–intron junctions (exon–intron circRNAs) (). Exonic circRNAs have been found in higher concentrations in cytoplasm compared to the nucleus showing capability of sponging microRNAs (miRNAs) and so can positively affect the expression of target genes leading to their overexpression. Unlike the first type, the other types are more concentrated in the cell nucleus and thus regulate gene expression at the primary steps of transcriptional and posttranscriptional levels (, ). CircRNAs have been widely detected in different cells, tissues, and organisms and also during various stages of organism development, playing a role in controlling cell growth and stress (). Through their regulatory mechanisms in the cell cycle, circRNAs have been found to apply surveillance on eukaryotic cell proliferation and homeostasis. Consistent with these findings, dysregulation of circRNAs has been reported in a vast number of proliferative disorders like different tumors. Bladder cancer (BCa) is an example in which the role of aberrantly expressed circRNAs in tumor development and progression has been studied. Similar to other malignancies, response to treatment in BCa requires early diagnosis which also guarantees better prognosis for the patients. CircRNAs not only have acted as potential biomarkers for BCa with promising characteristics in diagnosis and prediction of prognosis in BCa patients but also have been suggested as therapeutical targets in fighting against malignancy. In this review, we aim to outline the latest findings about the role of circRNAs in BCa.
CircRNAs in BCa
Upregulated CircRNAs in BCa
In expression analyses via high-throughput technologies like microarray and sequencing and also in quantitative PCR studies, a number of circRNAs have been found to be upregulated in samples taken from patients with BCa compared to healthy controls. These kinds of circRNAs are suggested as oncogenes with carcinogenic roles. Accordingly, their overexpressed levels have been shown to promote tumor cell proliferation and invasion in cell studies and also in vivo experiments, while their downregulation or knockdown reverses these effects.
Microarray analysis provides a possibility to screen a large number of aberrantly expressed circRNA candidates in a single platform. CircRNA_0058063 is an example which was reported recently by Liang et al. () as an upregulated circRNA in cancerous tissues of BCa patients compared to adjacent normal tissues. Microarray results revealed 312 aberrantly expressed circRNAs including 195 upregulated and 117 downregulated ones. CircRNA _0058063 showed a significantly increased expression in both BCa cell lines and tissues. A reverse correlation was seen between circRNA _0058063 expression level and overall survival (OS) in patients. Consistent with expectations, circRNA _0058063 knockdown suppressed tumor cell proliferation and metastasis in BCa BIU-87 cell lines. CircRNA_0058063 was found to act as a miRNA sponge to decrease the expression level of miR-486-3p by making interaction via a complementary sequence and induction of silencing. miR-486-3p inhibits the expression of the FOXP4 transcription factor which promotes tumorigenicity in various cancers.
Li et al. () using high-throughput sequencing found a number of upregulated RNA transcripts including long non-coding RNAs (lncRNAs), protein-coding mRNAs, and 34 circRNAs in 20 BCa tissues compared with a matched number of adjacent normal bladder tissues in addition to another set of transcripts which were downregulated. In GO and KEGG pathway enrichment analyses, dysregulated RNAs were associated with several signaling pathways controlling different critical cellular processes particularly DNA replication and cell cycle which play a role in the pathogenesis of BCa. In addition, 3 circRNAs including circPGM5 and circKIAA1462 were validated by qPCR. CircRNA PGM5 was demonstrated in the competing endogenous RNA (ceRNA) network to possess recognition sites for miRNAs associated with BCa along with lncRNA MIR194-2HG and AATBC.
Also, robust next-generation sequencing (NGS) technique and confirmatory qRT-PCR have been used to screen dysregulated circRNAs in BCa samples (). A significant differential expression of a single circRNA is assessed in BCa tissues relative to adjacent normal tissues via quantitative reverse transcription polymerase chain reaction (qRT-PCR; also known as real-time RT-PCR). An increasing number of circRNAs have been reported in separate studies to be aberrantly expressed in BCa tissues or in serum or urine samples of patients; thus, these circRNAs have been suggested as potential diagnostic and prognostic biomarkers for BCa patients (). Hsa-circRNA-403658 is a good instance for a series of circRNAs found to be upregulated in BCa tissues via the latter method. Wei et al. () demonstrated a differential expression of a number of circRNAs in BCa SW780, 5637, T24, J82, and RT4 cell lines cultured in hypoxic conditions in comparison with CCC-HB-2 healthy bladder epithelial cells using circRNA microarray. Hsa-circRNA-403658 was one of these circRNAs which showed the highest level of increased expression in further evaluation by qRT-PCR assay. Clinical samples of patients with BCa in which higher levels of hsa-circRNA-403658 were seen showed poorer prognosis, larger tumor size, increased metastasis, and higher clinicopathological stage (TNM staging) compared to patients with lower hsa-circRNA-403658 expression levels. As expected, hsa-circRNA-403658 knockdown using specific silencing RNA (siRNA) inhibited circRNA tumorigenic effects. Furthermore, in vitro and in vivo studies showed that hsa-circRNA-403658 controls the anaerobic glycolysis in hypoxic culture via enhancing the promotor activity and consequently positive regulation of lactate dehydrogenase A (LDHA) expression.
Computational studies and network analyses using bioinformatics methods have also facilitated the detection of differentially expressed circRNAs and their pathological roles and potential application as novel biomarkers for BCa (–), suggesting their application in early diagnosis and prediction of prognosis as well as their therapeutic potentials. Figure 1 demonstrates the role of circRNAs in modulating bladder cancer development via promoting glycolysis.
Figure 1
Table 1 outlines the most important circRNAs with an elevated expression level in the BCa cell line and also in patients’ samples.
Table 1
| CircRNA (other terms) | Clinical cases | Cell lines | Target genes/regulators/sponged miRNAs | Affected signaling pathway/process | Findings on overexpressed or silenced circRNA in BCa cellular experiments | Ref. (s) |
|---|---|---|---|---|---|---|
| Circ_0058063 | 94 BCa and matched NATs | HEK293 and BIU-87, 5637, and RT-112 | miR-486-3p/FOXP4 axis miR-145‐5p/CDK6 axis | – | Enhanced metastasis, correlation with higher disease stage | (, ) |
| Has_circRNA_403658 | 123 BCa patient tissues and matched NATs | CCC-HB-2 normal bladder epithelial cells and BCa SW780, 5637, T24, J82, and RT4 | LDHA | Glycolysis | Poorer prognosis, larger tumor size, increased metastasis, and higher clinicopathological stage | () |
| CircPDSS1 | 72 patient tissues and their NATs | HT-1197 and UMUC3 | miR-16 | – | Increased tumor cell proliferation, migration, and invasion | () |
| CircCASC15 (hsa_circ_0075828) | 67 patient tissues and control para-carcinoma tissues | 5637, J82, UM-UC-3, T24, and SW780 human BC cell lines and SV-HUC-1 human uroepithelial cell line | miR-1224-5p and CREB1 | – | Accelerated cell proliferation | () |
| CircRNA-MYLK | 32 patient tissues and control para-carcinoma tissues | EJ, T24, 5673, and BIU-87 BCa cell lines and 293T human embryonic kidney cells | miR-29a, VEGFA | Ras/ERK | Promoted cell proliferation, migration, and epithelial–mesenchymal transition (EMT) in vitro and enhanced angiogenesis and metastasis in xenografts | () |
| Hsa_circ_0001361 | 69 patient tissues and healthy bladder epithelial tissues as matched controls | EJ, UMUC3, RT4, 5637 human BCa cell lines, and SV-HUC-1 uroepithelial cell line | miR-491-5p, MMP9 | – | Facilitated in vitro and in vivo invasion and metastasis | () |
| Circ-VANGL1 | 87 BCa patient tissues and 37 NATs | T24, 253J, UMUC-3, J82, 5637, and EJ BCa cell lines and | miR-605‐3p/VANGL1 axis | – | Promoted in vitro cell proliferation, migration, and invasion and in vivo BCa propagation | () |
| CircTCF25 | 4 pairs of BCa tissues and matched NATs in microarray analysis and 40 pairs for qRT-PCR validation | T24 and EJ BCa cell lines | miR-103a-3p/miR-107/CDK6 axis | – | Promoted in vitro and vivo proliferation and migration | () |
| Hsa_circ_0137439 | Urine samples of 10 BCa patients and 10 healthy controls in microarray analysis and 116 BCa samples plus 30 healthy controls in qRT-PCR validation | T24 and 5637 human BCa cell lines | miR-142-5p/MTDH axis | – | Promoted BCa cell proliferation and metastasis | () |
| CircPTK2 (has-circ-0003221) | 40 BCa tissues and matched para-carcinoma NATs | T24 and 5637 BCa cell lines | – | – | Promoted BCa cell proliferation and migration | () |
| CircCEP128 | 40 BCa tissues and matched NATs | 293T, J82 and T24 BCa cell lines and SV-HUC-1 | miR-145-5p/MYD88 axis | MAPK | CircCEP128 silencing inhibited cell viability and mobility and stimulated apoptosis | () |
| Circ0001429 | 20 BCa tissues and matched NATs | T24 and 5637 SV-HUC-1 and BIU-87 | miR-205-5p/VEGFA axis | – | Enhanced propagation, migration, and invasion, and inhibited apoptosis | () |
| CircRGNEF | 90 BCa patient tissues and matched NATs | J82, EJ, T24, TCC, UM-UC-3, and RT-4 BCa cell lines and SV-HUC | miR-548/KIF2C axis | – | Promoted BCa cell proliferation, migration, and invasion | () |
| CircGPRC5a (hsa_circ_02838) | 20 early BCa, 40 advanced BCa samples, and 60 NATs | Bladder CSCs | circGprc5a-peptide/Gprc5a axis | – | Promoted self-renewal and invasion of bladder CSCs | () |
| Hsa_circ_0000144 | 69 BCa patient tissues and 21 matched NATs | T24, EJ, UMUC3, RT4, and 253J BCa cell lines and SV-HUC-1 cell line | miR-217/RUNX2 axis | – | Promoted in vitro and in vivo BCa cell proliferation and invasion | () |
| CircINTS4 | 40 BCa samples and 40 NATs | RT4, SW780, J82, 5637, T24, UMUC3 BCa cell lines, and SV-HUC | miR-146b/CARMA3 axis | NF-kB ↑ P38 MAPK ↓ | Increased in vitro and in vivo BCa tumorigenicity | () |
| CircZFR | 104 BCa samples and 40 NATs | UMUC3, T24, J82, 5637, SW780, EJ and BIU87 BCa cell lines, and CCC-HB-2 cells | miR-377/ZEB2 axis | – | Silencing showed inhibition of cell proliferation, migration, and invasion | () |
| CircASXl1 (hsa_circ_0001136) | 61 BCa samples and 40 NATs | – | – | – | Correlated with worse clinicopathological features in BCa patients and lower OS | () |
| Hsa_circ_0068871 | 32 BCa samples and 40 NATs | T24, UMUC3, EJ and J82 BCa cell lines and SV-HUC-1 | miR-181a-5p/FGFR3 axis | – | Promoted tumor cell growth | () |
| Circ_102336 | 64 BCa samples and 40 NATs | T24 and 5637 BCa cell lines and SV-HUC-1 and HEK-293 T cells | miR-515-5p | – | Promoted cell growth Enhanced drug sensitivity in circ_102336 knockdown | () |
| Hsa_circ_0068307 | 30 BCa samples and 40 NATs | EJ, T24, RT-4 and UM-UC-3 BCa cell lines | miR-147/c-Myc axis | – | Hsa_circ_0068307 knockdown inhibited BCa in vitro cell proliferation and migration and in vivo xenografts | () |
| Circ_0006332 | 32 BCa samples and 40 NATs | 5637, T24, J82, UM-UC-3, TSCCUP, and SV-HUC-1 BCa cell lines | miR-143/MYBL2 axis | – | Promoted in vivo cancer growth Circ_0006332 knockdown suppressed BCa cell proliferation and invasion | () |
| CircRNA-0071196 | 80 BCa tissues and 30 para-carcinoma tissues | 5637 BCa cell line | miR-19b-3p/CIT axis | – | CircRNA-0071196 silencing decreased BCa cell proliferation and migration | () |
| circZNF139 | – | UC3 and 5637 cells BCa cell lines | – | PI3K/AKT | ZNF139/circZNF139 promoted BCa cell proliferation, migration, and invasion | () |
| CircDOCK1 | 32 BCa samples and 32 NATs | BIU-87, EJ-m3, T24 and 5673 BCa cell lines and SV-HUC-1 cells | hsa-miR-132-3p/Sox5 axis | – | CircDOCK1 silencing suppressed BCa cell progression in vitro and xenograft growth in vivo | () |
| CircKIF4A (hsa_circ_0007255) | 50 BCa samples and 32 NATs | 5637, RT-112, and BIU-87 BCa cell lines and HEK293T cells | miR-375/1231/NOTCH2 axis | – | Promoted BCa in vitro cell proliferation and metastasis | () |
| Hsa_circ_0001944 | 90 BCa samples and 32 NATs | 5637, UM-UC-3, T24, and RT-4 BCa cell lines and SV-HUC-1 cells | miR-548/PROK2 axis | – | Silencing suppressed BCa cell proliferation and invasion in vitro and in vivo | () |
| CircPRMT5 | 119 BCa samples and 32 NATs | T24, TCC-SUP, 5637, and UM-UC-3 BCa cell lines, and SV-HUC-1 cells | miR-30c/SNAIL1/E-cadherin axis | – | Silencing decreased BCa cell migration, invasion in vitro, and metastasis in vivo Overexpression enhanced BCa cells EMT | () |
| CircGLIS3 (hsa_circ_0002874) | 48 BCa samples and 32 NATs | T24, UM-UC-3 BCa cell lines and SV-HUC-1 cells | miR-1273f/SKP1/cyclin D1 axis | Silencing inhibited BCa cell proliferation, invasion, and migration in vitro and cell growth in vivo Upregulation promoted G0/G1 phase of cell cycle through miR-1273f/SKP1/Cyclin D1 axis | () | |
| Hsa_circ_0041103 | 50 BCa samples and 32 NATs | T24, UM-UC-3, RT4, 5637 BCa cell lines, and SV-HUC-1 cells | miR-107/FOXK1 axis | – | Silencing inhibited BCa cell proliferation and metastasis | () |
| CircEHBP1 | 186 BCa samples and 32 NATs | UM-UC-3, T24, and 5637 BCa cell lines, and SV-HUC-1 cells | miR-130a-3p/TGFβR1/VEGF-D axis | TGF-β/SMAD | Promoted BCa lymph node metastasis in vivo | () |
| Circ_0000735 | 50 BCa samples and 32 NATs | 5637, RT-112 and BIU-87 BCa cell lines, and SV-HUC-1 cells | miR-502-5p | – | Knockdown suppressed BCa cell proliferation and invasion in vitro and tumorigenesis in vivo | () |
| Circ_100984 | 20 BCa samples and 32 NATs | HT-1376, HTB9, 253J, BT-B, Biu-87 and 5637 BCa cell lines and SV-HUC-1 cells | miR-432-3p/c-Jun/YBX-1/β-catenin axis | Wnt | Knockdown inhibited BCa cell growth, invasion, metastasis, and EMT in vivo and in vivo | () |
| circRIMS1 (hsa_circ_0132246) | 20 BCa samples and 32 NATs | J82, 5637, T24, EJ, and TCCSUP BCa cell lines and SV-HUC-1 and HEK-293 cells | miR-433-3p/CCAR1/c-Myc axis | – | Knockdown repressed BCa cell proliferation, invasion, and metastasis in vivo and tumor growth in vivo | () |
| CircSEMA5A | 40 BCa samples and 32 NATs | T24, UM-UC-3, 5637, J82 BCa cell lines, and SV-HUC-1 cells | miR-330-5p/ENO1 axis | Glycolysis ↑ | Promoted BCa cell proliferation, invasion, migration capabilities, and angiogenesis in vivo | () |
| CircRNA_100146 (hsa_circRNA_100146) | 68 BCa samples and 32 NATs | J82, 5637, SW780, and T24 BCa cell lines, and HCV-29 cells | miR-149-5p/RNF2 axis | – | Promoted BCa cell proliferation, invasion, and migration and inhibited apoptosis | () |
| CircBC048201 | 30 BCa samples and 32 NATs | UM-UC-3 BCa cell lines and SV-HUC-1 cells | miR-1184/ITGA3 axis | – | Interference inhibited BCa cell proliferation, migration, and invasion | () |
| CircRNA_0071196 | 80 BCa samples and 30 matched para-carcinoma tissues | The 5637 human BCa cell line | miR-19b-3p/CIT axis | – | Knockdown repressed BCa cell proliferation and migration | () |
| Circ_0061140 | 42 BCa samples and corresponding NATs | T24, 253j, 5637, J82, RT4, UMUC3 BCa cell lines, and SV-HUC-1 cells | miR-1236 | – | Circ_0061140 knockdown repressed BCa cell proliferation and invasion | (57) |
| Circ_001418 | – | – | miR-1297/EphA2 axis | – | Enhanced BCa cell proliferation and invasion, and decreased apoptosis | (58) |
| Circ_0067934 | 54 BCa tissues and corresponding NATs | T24, RT4 and UMUC3 BCa cell lines, and SV-HUC-1 cells | miR-1304-Myc axis | – | Circ_0067934 silencing inhibited BCa cell proliferation, invasion, and migration in vivo | (59) |
| Hsa_circ_0017247 | 50 BCa tissues and corresponding NATs | UM-UC3, SW780, BIU, and J82 BCa cell lines | – | Wnt/β-catenin | Knockdown inhibited BCa cell growth and promoted apoptosis in vitro and repressed tumor growth in vivo | (60) |
| CircFNTA | 41 BCa tissues and corresponding NATs | T24, J82, 5637, and UMUC3 BCa cell lines, and SV-HUC cells | miR-370-3p/FNTA axis | KRAS | Enhanced cell invasion and chemo-resistance to cisplatin in BCa cell lines CircFNTA knockdown repressed its tumorigenic effects | (61) |
| CircRIP2 | 58 BCa tissues and corresponding NATs | 5637 and UM-UC-3 BCa cell lines | miR-1305 | Tgf-β2/smad3 | Increased BCa cell progression through stimulation of EMT | (62) |
| CircUVRAG | Experiment was conducted on 20 BALB/c nude mice | T24, EJ, J82, UM-UC-3, TCC, and RT-4 BCa cell lines, and SV-HUC cells | miR-223/FGFR2 axis | – | Knockdown repressed BCa cell proliferation and metastasis in vitro and in vivo | (63) |
| Circ-BPTF | 72 BCa tissues and corresponding NATs | UM-UC-3 and T24 BCa cell lines | miR-31-5p/RAB27A axis | – | Increased in vitro and in vivo progression of BCa cells | (64) |
| Circ_0023642 | – | J82 and UMUC3 BCa cell lines | miR-490-5p | ERα/circ_0023642/miR-490-5p/EGFR | ERα suppressed BCa cell invasion in vitro through downregulation of circ_0023642 via expressional modulation of UVRAG host gene and also repressed metastasis in vivo | (65) |
Upregulated circRNAs in BCa.
↑, activation or increased level; ↓, inhibition or decreased level; NAT, normal adjacent tissue.
VEGFA, vascular endothelial growth factor A; MMP9, matrix metallopeptidase 9; MTDH, metadherin; CSCs, cancer stem cells; IGFIR, type 1 insulin-like growth factor receptor; ERα, estrogen receptor alpha.
Downregulated CircRNAs in BCa
These kinds of circRNAs have been found to exhibit lower expression levels in BCa samples compared to normal adjacent tissues. They are suggested to play a role as tumor suppressors with biological functions controlling the critical cellular processes cell proliferation and extracellular matrix stability and so their downregulation in a set of studies has been shown to facilitate tumor cell proliferation, migration, and invasion. In vivo experiments have also demonstrated accelerated tumor progression in the presence of decreased expression of these circRNAs. Similar to the former circRNAs, these kinds have been linked with cell cycle regulation through different miRNA–protein axes, among which are some oncogenes or tumor-suppressor genes which are dysregulated. Bioinformatic analyses, RNA pull-down assays, and luciferase reporter assays have shown single or several miRNAs being sponged in close interaction with circRNAs. The expression of these miRNAs is mainly suppressed via upstream circRNAs, and they themselves regulate some actions through affecting downstream molecules. Yet, some miRNAs act upstream of circRNAs exerting a regulatory role on them. Downregulated circRNAs are mainly located in the cytoplasm, so it is suggested that they play their regulatory roles at posttranscriptional or translational steps.
For instance, circSLC8A1 is a circRNA which has been reported by Lu et al. (66) to be downregulated in BCa tissues compared to healthy adjacent tissues in a study of 70 patients diagnosed with BCa. They detected a number of aberrantly expressed circRNAs through RNA sequencing. qRT-PCR confirmed a decreased expression of circSLC8A1 in 81% (57/70) of total BCa tissues compared to their matched adjacent tissues. Expression assay in 6 BCa cell lines using qRT-PCR also showed a decreased expression of circSLC8A1 compared to SV-HUC-1 normal bladder cells.
In vitro analyses revealed suppression of tumorigenic impacts following circSLC8A1 overexpression in BCa cell lines. By using different prediction tools, it was demonstrated that circSLC8A1 potentially sponges 7 miRNAs, among which were miR-130b and miR-494 whose interactions with circSLC8A1 were confirmed by RNA pull-down assay and biotin labeling. Overexpression of both miRNAs was associated with oncogenesis in BCa cells. Furthermore, luciferase reporter assay and Western blotting analysis demonstrated that miRNAs can bind to the 3′ end of the phosphatase and tensin homolog (PTEN) tumor suppressor and inhibit its expression. Rescue experiments and immunohistochemistry (IHC) analysis showed that circSLC8A1 acts as a tumor suppressor via the miR-130b and miR-494/PTEN/PI3k/Akt signaling axis. Table 2 summarizes the recent findings of tumorigenicity studies on downregulated circRNAs in BCa. Figure 2 represents the role of several circRNAs in bladder cancer cells via regulating some key signaling cascades.
Table 2
| circRNA (other terms) | Clinical cases | Cell lines | Target genes/regulators/sponged miRNAs | Affected signaling pathway/process | Findings on overexpressed or downregulated circRNA in BCa cellular experiments | Ref. (s) |
|---|---|---|---|---|---|---|
| CircBCRC-3 | 47 BCa patient tissues and matched NATs | BC and EJ BCa cell lines and SV-HUC-1 cells | miR-182-5p/p27 axis | – | Overexpression inhibited BCa cell growth in vitro and tumor progression in vivo | (67) |
| CircFUT8 | 145 BCa patient tissues and 50 matched NATs | T24 and UM-UC-3 BCa cell lines and SV-HUC-1 cells | miR-570-3p/KLF10 axis | – | Overexpression suppressed BCa cell migration and invasion in vitro and metastasis in vivo | (68) |
| BCRC4 (hsa_circ_001598) | 24 BCa patient tissues and matched NATs | UMUC3 BCa cell lines and SV-HUC-1 cells | miR-101/EZH2 axis | – | Overexpression decreased BCa cell proliferation and also, increased apoptosis | (69) |
| CircSLC8A1 | 70 BCa patient tissues and matched NATs | 5637, T24, J82, EJ, UMUC, and RT4 BCa cell lines, and SV-HUC-1 cells | miR-130b and miR-494/PTEN/PI3k/Akt signaling axis | PI3k/Akt | Overexpression decreased BCa cell migration and invasion in vitro CircSLC8A1 inhibited tumor progression in vivo | (66) |
| Hsa_circ_0077837 and Hsa_circ_0004826 | 70 BCa patient tissues and matched NATs | EJ, 5637, and T24 BCa cell lines and SV-HUC-1 cells | – | – | Overexpression inhibited BCa cell proliferation, migration, and invasion | (70) |
| CircACVR2A (hsa_circ_0001073) | 140 BCa patient tissues and matched NATs | T24, UM-UC-3, RT4, J82, 5637, HT-1376, TCCSUP BCa cell lines, and SV-HUC-1 cells | miR-626/EYA4 axis | – | Overexpression inhibited BCa cells proliferation, migration, and invasion in vitro and tumor progression and metastasis in vivo | (71) |
| Hsa_circ_0002024 | 20 BCa patient tissues and matched NATs | EJ, 5637, T24, and UMUC-2 and normal human urothelial cells | miR-197-3p | – | Upregulation suppressed BCa cells proliferation, migration, and invasion | (72) |
| Circ-FOXO3 | 49 BCa patient tissues and matched NATs | EJ and T24 BCa cell lines | miR-9-5p/TGFBR2 axis | – | Upregulation suppressed BCa cells proliferation, migration, and invasion | (73) |
| 30 BCa patient tissues and matched NATs | T24, UM-UC-3 and J82 BCa cell lines, and SV-HUC-1 cells | miR-191-5p | – | Overexpression increased apoptosis | (74) | |
| CircNR3C1 (Hsa_circ_0001543) | 42 BCa patient tissues and matched NATs | T24, EJ, UMUC3, J82, 5637 BCa cell lines, and SV-HUC-1 cells | -miR-23a-3p -miR-27a-3p/cyclin D1 axis | – | Upregulation suppressed BCa cells proliferation and progression in vitro and in vivo via arrest in the G0/G1 phase | (75) |
| CircMTO1 | 117 BCa patient tissues and matched NATs | UMUC3, SVHUC1, T24, J82, and 5637 and CCC-HB-2 cells | miR-221 | – | Overexpression inhibited BCa cell migration and invasion in vitro and progression in vivo | (76) |
| Circ-ITCH | 72 BCa patient tissues and matched NATs | 5637, T24, J82, EJ, UMUC, TCC, 253J, and RT4 BCa cell lines and SV-HUC cells | -miR-224 -miR-17/p21 and PTEN axis | – | Downregulated circ-ITCH inhibited BCa cell proliferation, migration, and invasion in vitro via induction of the G1/S phase arrest Tumor progression was suppressed in vivo | (77) |
| CircST6GALNAC6 | 30 BCa patient tissues and matched NATs | T24, J82, UM-UC-3, 5637, and SW780 and SV-HUC-1 cells | miR-200a-3p/STMN1 signaling axis | – | Overexpression suppressed BCa cell proliferation and migration in vitro and metastasis in vivo | (78) |
| Circ_0071662 | 97 BCa patient tissues and matched NATs | BIU-87, T-24, EJ-28, and J82 BCa cell lines and SV-HUC-1 cells | miR-146-3p | – | Overexpression inhibited BCa cell proliferation and invasion | (79) |
| Hsa_circ_0018069 | 41 BCa patient tissues and matched NATs | T24, and Biu-87 BCa cell lines and SV-HUC-1 cells | miR-23c, miR-34a-5p, miR-181b-5p, miR-454-3p, and miR-3666 | – | Downregulation correlated with more severe clinicopathological features | (80) |
| CircPICALM | 168 BCa patient tissues and 40 NATs | T24, UM-UC-3, J82, and RT-4 BCa cell lines and SV-HUC-1 cells | miR-1265/STEAP4/pFAK-Y397 axis | – | Overexpression suppressed BCa cell invasion in vitro and metastasis in vivo | (81) |
| Hsa_circ_0091017 | 40 BCa patient tissues and corresponding NATs | 5637, EJ, T24, UMUC-3, RT4 BCa cell lines, and SV-HUC-1 cells | miR-589-5p | – | Overexpression suppressed BCa cell proliferation, migration, and invasion | (82) |
| Circ-ZKSCAN1 | 68 BCa patient tissues and matched NATs | T24, UM-UC-3, 5637, and EJ BCa cell lines and SV-HUC-1 cells | miR-1178-3p/p21 axis | Overexpression suppressed BCa cell proliferation, migration, and invasion in vitro and also tumor progression and invasion in vivo | (83) | |
| CircHIPK3 | 44 BCa patient tissues and matched NATs | T24T and UMUC BCa cell lines and SV-HUC-1 and HUVEC normal bladder cells | miR-558/HPSE axis | Angiogenesis | Overexpression repressed BCa cell migration and invasion in vitro and also tumor progression, metastasis, and angiogenesis in vivo | (84) |
| CircFAM114A2 | 31 BCa patient tissues and matched NATs | T24, J82, 5637, and 293T BCa cell lines and SV-HUC-1 cells | miR-762/△NP63 axis | – | Overexpression suppressed BCa cell proliferation, migration, and invasion in vitro and tumor growth in vivo | (85) |
| CircPTPRA | 104 BCa patient tissues and matched NATs | T24 and UM-UC-3 BCa cell lines and SV-HUC-1 and HEK-293T cells | miR-636/KLF9 axis | – | Overexpression suppressed BCa cell proliferation and knockdown promoted it in vitro and tumor growth in vivo | (86) |
| CiRs-6 | 45 BCa patient tissues and matched NATs | T24 and UM-UC-3 BCa cell lines | miR-653/March1 axis | – | Overexpression inhibited BCa cell proliferation in vitro and tumor growth in vivo | (87) |
| CircFNDC3B | 82 BCa patient tissues and 56 matched NATs | T24 and UM-UC-3 BCa cell lines and SV-HUC-1 cells | miR-1178-3p/G3BP2 axis | – | Overexpression repressed BCa cell proliferation, migration, and invasion in vitro and inhibited tumor growth and metastasis in vivo | (88) |
| CircUBXN7 (hsa_circ_0001380) | 30 BCa patient tissues and matched NATs | T24, J82, EJ, RT4, and UM-UC-3 BCa cell lines and SV-HUC-1 cells | miR-1247-3p/B4GALT3 axis | – | Downregulation correlated with more severe clinicopathological features in BCa patients Overexpression suppressed BCa cell proliferation, migration, and invasion in vitro and tumor progression in vivo | (89) |
| CircCDYL | 30 BCa patient tissues and matched NATs | EJ and T24T BCa cell lines and SV-HUC-1 cells | c-Myc | – | Overexpression repressed BCa cell proliferation and migration in vitro | (90) |
| Circ5912 | 45 BCa patient tissues and matched NATs | T24 and SW780 BCa cell lines | – | TGFβ | Knockdown increased BCa cell proliferation and invasion in vitro Overexpression decreased EMT through suppression of TGF-β2 | (91) |
| CircRBPMS | 90 BCa patient tissues and matched NATs | RT4, UM-UC-3, T24, 5637, and J82 BCa cell lines and SV-HUC-1 cells | miR-330-3p/RAI2/EMT-ERK axis | KRAS/ERK | Overexpression suppressed BCa cell proliferation and invasion in vitro and tumor progression and metastasis in vivo | (92) |
| CircLPAR1 (hsa_circ_0087960) | 68 BCa patient tissues and matched NATs | 5637 and T24 BCa cell lines and 293 cells | miR-762 | Knockdown increased BCa cell invasion | (93) | |
| CircRNA_000285 (hsa_circ_0000285) | 146 BCa patient tissues and 98 matched NATs | HTB-9, T24, J82, SW780, and RT4 BCa cell lines and CCC-HB-2 normal bladder cells | – | – | Lower level was seen in chemoresistance to cisplatin | (94) |
| Cdr1as | 32 BCa patient tissues and matched NATs | TCCSUP, 5367, T24, and EJ BCa cell lines | miR-1270/APAF1 axis | – | Cdr1as improved BCa cell’s chemosensitivity to cisplatin in vitro and in vivo Overexpression increased apoptosis in BCa cells | (95) |
Downregulated circRNAs in BCa.
Figure 2
Diagnostic and Prognostic Values of CircRNA in BCa
As explained above, dysregulated circRNAs cause disturbance in the cellular proliferation leading to malignancies, particularly BCa. On the other side, in the majority of the studies, dysregulation in circRNA expression has been statistically correlated with unfavorable clinicopathological features including high tumor size, histological grade, pathological stage, and presence of distant or lymph node metastasis in uni- or multivariate analyses in BCa patients. Therefore, as a consequence, it has been found that a dysregulation in the circRNA level can predict poorer survival (in terms of overall survival (OS), recurrence-free survival (RFS), disease-free survival (DFS), or progression-free survival (PFS)) and worse prognosis in Kaplan–Meier analyses.
As an example, it was formerly stated that hsa_circRNA_403658 is upregulated in BCa tissues compared to adjacent tissues (). Kaplan–Meier analysis for the evaluation of survival showed that a high level of hsa_circRNA_403658 expression correlates with shorter survival in BCa patients. Implementation of the χ2 test to assess the association between circRNA expression and clinicopathological features has revealed a positive correlation between high hsa_circRNA_403658 expression and malignant characteristics including higher tumor volume (size ≥3 cm related to <3 cm), metastasis to distant places and advanced TNM stage (III–IV). In the univariate and multivariate Cox regression test for assessment of prognostic factors, it was demonstrated that hsa_circRNA_403658 is an independent factor for prediction of prognosis in BCa patients ().
In another study (70), downregulated circRNAs hsa_circ_0077837 and hsa_circ_0004826 in BCa were found to be significantly associated with worse OS and RFS in BCa patients in Kaplan–Meier analysis. Univariate and multivariate Cox regression analyses confirmed that both circRNAs can act as independent prognostic factors compared to other factors in BCa patients. The area under the curve (AUC) for assessment of prognostic power of circRNAs revealed 0.775 and 0.790 values for hsa_circ_0077837 and hsa_circ_0004826, respectively, showing acceptable measures and suggesting their potentials as reliable biomarkers for prediction of worse prognosis in BCa patients.
Among other circRNAs, circASXL1 has been reported to have sensitivity and specificity of 0.686 and 0.769, respectively, which suggests its reliable diagnostic power in distinguishing the BCa patients from healthy people (). A number of circRNAs whose prognostic or diagnostic values have been studied in BCa are shown in Table 3.
Table 3
| Description | Area under curve | Sensitivity | Specificity | Kaplan–Meier analysis | Univariate Cox regression | Multivariate Cox regression | Other correlation tests | Ref. (s) |
|---|---|---|---|---|---|---|---|---|
| Hsa_circRNA_403658 upregulation in BCa patients | – | – | – | hsa_circRNA_403658 high expression correlated with shorter survival in BCa patients. | Increased hsa_circRNA_403658 level was correlated with advanced clinicopathological features such as increased tumor size(≥3 cm), metastasis to distant places, and malignant TNM stage(III–IV). | Increased hsa_circRNA_403658 level was correlated with advanced clinicopathological features including larger tumor size(≥3 cm), lymph node metastasis, distant metastasis, and malignant TNM stage (III-IV). | χ2 test showed a positive correlation between high hsa_circRNA_403658 expression and malignant clinicopathological features including larger tumor size, advanced tumor TNM stage, and distant metastasis. | () |
| hsa_circRNA_403658 can act as an independent prognostic factor for BCa patients | ||||||||
| Hsa_circ_0003221 (circPTK2) upregulation in tissue and blood samples of BCa patients | – | – | – | – | – | – | Student’s t test showed that the expression level is correlated with tumor size, lymph node metastasis, and T stage at BCa patients (p < 0.05) | () |
| Hsa_circ_0072995 (circRGNEF) upregulation in BCa patients | – | – | – | – | – | – | High expression level was positively correlated with lymph node metastasis, high T stage, and advanced grades of BCa and also associated with worse prognosis. | () |
| CircGprc5a upregulation in BCa patients | – | — | – | High circGprc5a expression correlated with poorer survival and prognosis in BCa patients. | – | – | – | () |
| CircZFR upregulation in BCa patients | 0.8216 | – | – | Higher circZFR correlated with poorer prognosis and survival in BCa patients. | circZFR expression correlated with worse PFS and OS. | The chi-square tests showed correlation between circZFR expression and tumor stage, grade, lymph node metastasis, and recurrence in BCa patients. | () | |
| CircASXL1 upregulation in BCa patients | 0.770 | 0.686 | 0.769 | BCa patients with higher levels of circASXL1 levels had poorer OS. | High circASXL1 expression correlated with more severe clinicopathological features including higher tumor grade, pathological T stage, distant, and lymph node metastasis. | High circASXL1 expression correlated with malignant clinicopathological features including advanced pathological T stage, distant and lymph node metastasis. | – | () |
| Hsa_circ_0001944 upregulation in BCa patients | – | – | – | High Hsa_circ_0001944 expression correlated with worse prognosis in BCa patients. | – | – | The Pearson’s correlation test showed correlation between hsa_circ_0001944 higher expression and larger tumor size, advanced T stage, higher grade, and lymph node metastasis in BCa patientsAlso, poorer prognosis was predicted for patients with higher hsa_circ_0001944 levels. | () |
| CircPRMT5 upregulation in BCa patients | – | – | – | BCa patients with high circPRMT5 or miR-30c expression exhibited poorer survival rate. Correlated with worse prognosis. | – | – | The x2 test showed that circPRMT5 serum and urine levels in BCa patients are associated with metastasis. | () |
| Hsa_circ_0041103 upregulation in BCa patients | – | – | – | Hsa_circ_0041103 expression correlated with unfavorable OS in BCa patients. | – | – | The two-paired independent t-test demonstrated positive correlation between high levels of hsa_circ_0041103 and advanced clinicopathological features including larger tumor size, higher pathological T stage, and lymph node metastasis in BCa patients. | () |
| cTFRC upregulation in BCa patients | – | – | – | Patients with higher cTFRC expression level had poorer OS. | – | – | cTFRC expression was positively correlated with advanced tumor T stage, higher grade and lymphatic invasion at BCa patientscTFRC was associated with poor prognosis. | (96) |
| Circ_0061140 upregulation in BCa patients | – | – | – | BCa patients with high circ_0061140 expression exhibited worse prognosis compared to those with lower levels. | – | – | The χ2 test showed correlation between high circ_0061140 levels and lymph node or distant metastasis. | (57) |
| Circ_0067934 upregulation in BCa patients | – | – | – | BCa patients with high circ_0067934 level had shorter 5-year OS and disease-free survival. | – | – | The χ2 test showed a positive correlation between high circ_0067934 levels and advanced clinicopathological features including tumor size, higher pathological stage, and lymph node metastasis. | (59) |
| Circ-BPTF upregulation in BCa patients | – | – | – | Patients with higher circ-BPTF expression level had worse OS. | – | – | High cTFRC expression was positively correlated with advanced tumor stage and recurrence in BCa patients. | (64) |
| CircFUT8 downregulation in BCa patients | – | – | – | Lower circFUT8 levels in BCa patients correlated with worse OS and poor prognosis. | – | – | The chi-square test demonstrated an association between low circFUT8 expression and worse clinicopathological features including lymph node metastasis and high histological grade. | (68) |
| Hsa_circ_0077837 and Hsa_circ_0004826 downregulation in BCa patients (low: 35 for both and high: 35 for both) | 0.775 and 0.790 for hsa_circ_0077837 and hsa_circ_0004826, respectively | – | – | Downregulated hsa_circ_0077837 and hsa_circ_0004826 were associated with lower OS and RFS in BCa patients. | Correlation between high expression of both circRNAs, tumor stage, grade, and lymph node metastasis with shorter OS and RFS in BCa patients. | Correlation between high expression of both circRNAs and lymph node metastasis with shorter OS, and also high expression of hsa_circ_0077837 and lymph node metastasis with shorter RFS in BCa patients. | – | (70) |
| Both circRNAs can act as independent factors for prediction of prognosis in BCa patients. | ||||||||
| CircACVR2A downregulation in BCa patients | – | – | – | Low circ-BPTF expression level was associated with worse OS and prognosis in BCa patients. | – | – | Chi-square test showed correlation between low circACVR2A expression and advanced tumor stage, grade, and lymph node metastasis in BCa patients. | (71) |
| Circ-ITCH downregulation in BCa patients | – | – | – | Lower circ-ITCH level positively correlated with shorter OS and poorer prognosis in BCa patients. | – | – | Downregulated circ-ITCH was significantly associated with high pathological tumor stage in BCa patients. | (77) |
| Circ_0071662 downregulation in BCa patients | – | – | – | Circ_0071662 expression was positively correlated with survival rate in BCa patients. | – | – | Low Circ_0071662 expression correlated with lymph node and distal metastasis and poorer prognosis in BCa patients. | (79) |
| Hsa_circ_018069 downregulation in BCa patients (diminished in 80.5% (33/41) of cases) | 0.709 | 0.976 | 0.463 | – | – | – | The Student’s t-test showed that hsa_circ_018069 downregulation correlated with more severe clinicopathological features including high tumor grade, pathological T stage, and tumor muscular invasion. | (80) |
| CircPICALM downregulation in BCa patients | – | – | – | BCa patients with a diminished level of circPICALM exhibited poorer OS related to those with high levels. | circPICALM expression, histological grade, pathological T stage, and lymph node metastasis correlated with survival in BCa patients. | circPICALM expression and lymph node metastasis demonstrated as independent features for prediction of prognosis in BCa patients. | The chi-square test showed that circPICALM downregulation correlated with unfavorable clinicopathological features including high histological grade, pathological T stage, and lymph node metastasis in BCa patients. | (81) |
| Circ-ZKSCAN1 downregulation in BCa patients | – | – | – | Downregulated circ-ZKSCAN1 correlated with worse OS and disease-free survival and predict poorer prognosis for BCa patients. | – | – | The chi-square test demonstrated an association between low circ-ZKSCAN1 levels and advanced clinicopathological features including high histological grade, pathological T stage, and lymph node metastasis in BCa patients. | (83) |
| CiRs-6 downregulation in BCa patients | – | – | – | Higher ciRs-6 was positively correlated with good OS in BCa patients. | – | – | One-way ANOVA test showed that higher ciRs-6 expression was associated with lower tumor grade, pathological T stage, and better prognosis in BCa patients. | (87) |
| Hsa_circ_0018069 downregulation in BCa patients | 0.709 | 0.976 | 0.463 | – | – | – | The Student’s t-test showed correlation between low hsa_circ_0018069 levels and clinicopathological features including higher tumor grade, advanced T stage, and muscular invasion depth in BCa patients. | (80) |
| CircUBXN7 downregulation in BCa patients | – | – | – | Patients with decreased circUBXN7 levels showed shorter OS. | – | – | The chi-square analysis showed correlation between low circUBXN7 expression and advanced pathological T stage and more severe grades in BCa patients. | (89) |
| Circ5912 downregulation in BCa patients | – | – | – | Patients with higher circ5912 expression had longer OS compared to those with lower levels. | – | – | The one-way ANOVA test showed correlation between higher levels of circ5912 and favorable clinicopathological features including lower tumor grade, stage, and metastasis in BCa patients. | (91) |
| CircFNDC3B downregulation in BCa patients | – | – | – | Patients with lower circFNDC3B levels showed decreased survival. | – | – | The chi-square test revealed a positive correlation between lower circFNDC3B levels and highly advanced clinicopathological features such as higher histological grade, T stage, and metastasis to lymph nodes. | (88) |
| Circ-ITCH downregulation in BCa patients | – | – | – | Low circ-ITCH levels in BCa patients were positively correlated with poorer OS. | – | – | The chi-square test showed a correlation between low circ-ITCH expression level and more advanced tumor grade in BCa patients. | (77) |
| Hsa_circ_0000285 downregulation in BCa patients | Higher hsa_circ_0000285 expression was associated with longer OS in BCa patients. | hsa_circ_0000285 level correlated with prognosis in BCa patients. | hsa_circ_0000285 level is an independent prognostic factor for BCa patients. | The chi-square demonstrated correlation between hsa_circ_0000285 expression and clinicopathological features. | (94) | |||
| CircLPAR1 downregulation in BCa patients | – | – | – | BCa patients with low circLPAR1 levels had decreased survival compared to those with higher levels. | A correlation was seen between low circLPAR1 levels and decreased DSS in BCa patients. | – | (93) | |
An overview to the diagnostic and prognostic values of dysregulated circRNAs in BCa.
OS, overall survival; RFS, recurrence-free survival; DDS, disease-specific survival.
Discussion
Circular RNAs (circRNAs) are covalently closed nucleic acid strands which are classified as non-coding RNAs and mainly do not code any protein. They have been found to play a role in gene regulation in several stages. CircRNAs show cell-, tissue-, or species-specific tropism and are known to be dysregulated in tissues in a number of cancers. They have been found to either act as tumor suppressors or exhibit oncogenic roles on overexpression. The causative mechanisms of circRNAs’ role in tumorigenicity are vastly being studied. Their dysregulation has mainly been associated with disturbances in cell cycle regulation through activation of several signaling pathways.
In this review, we summarized a number of studies conducted on dysregulated circRNAs in BCa. Dysregulation includes any increase or decrease in circRNA expression levels in BCa tissues or cell studies compared to normal adjacent tissues. To assess the circRNA dysregulation, some high-throughput technologies like RNA sequencing and confirmatory qRT-PCR have been employed. Upregulated circRNAs in the first section (Table 1) have been found to accelerate tumor cell proliferation and enhance migration and invasion of cancer cell in vitro. In vivo studies have shown increased tumor progression when these circRNAs are overexpressed. Suppression of upregulated circRNAs via specific siRNAs in BCa has confirmed repression of proliferative and migratory potential following their silencing.
Downregulated circRNAs (Table 2), on the other hand, have been known to exert their anti-tumorigenic roles via suppression of tumor cell proliferation, migration, invasion, and metastasis. Overexpression experiments have confirmed tumor-suppressing roles of the second class of circRNAs via diminishing tumor cell malignant behaviors.
Furthermore, correlation studies have shown a significant association between dysregulated circRNA expression levels and worse clinicopathological features including higher tumor size, distant or lymph node metastasis, higher histological grade, pathological stage, and advanced TNM stage in BCa patients (Table 3). Statistical analyses have also demonstrated that dysregulation of circRNAs can be used as independent prognostic factors for BCa patients. Acceptable AUC, specificity, or sensitivity values in diagnostic analyses have revealed the diagnostic power of circRNAs in distinguishing BCa from other diseases. Taken together, circRNAs have been suggested as markers with reliable prognostic and diagnostic potential which can be used as biomarkers in either diagnosis or prediction of prognosis in BCa patients. Not only circRNAs but also other ncRNAs like lncRNAs have shown high stability in biological fluids, making them good biomarkers with easy detection for a number of human diseases particularly diverse types of cancers including BCa, breast cancer, hepatocellular carcinoma, and colorectal cancer (97, 98). Exosomes as extracellular vesicles involved in cellular communications are particularly shown to contain circRNAs in high concentrations and in a stabile form (99). These membranes can be beneficial in the detection of malignancies when derived from cancer cells spreading to blood and detectable in serum. Newly identified circRNAs have been introduced through high-throughput approaches such as next-generation sequencing (NGS), and microarray analysis, which make the huge identification of ncRNAs possible, while qRT-PCR is the main technique with potential in clinical diagnosis and quantification of circRNAs for both prognostic and diagnostic goals, and it is also used as the confirmatory method upon a novel ncRNA as previously reported (100). Vast application of qRT-PCR in quantification of a circRNA, however, is possible when the junction/fusion site is identified (). Moreover, other technological drawbacks require to be addressed for clinical applications of circRNAs.
In vitro and xenograft studies have confirmed the suitability of circRNAs as therapeutic targets in cancers. However, several issues such as biosafety ones should be solved before application of circRNA-targeting methods in clinical settings.
Taken together, although circRNAs have shown roles in the development and progression of various human cancers, and their quantification have demonstrated excellent potential in distinguishing patients with BCa from healthy individuals, it seems that application of circRNAs as novel biomarkers needs further investigations, more time, and addressing of technological problems to enter in clinical settings.
Publisher’s Note
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Statements
Author contributions
SGF and SN wrote the draft and revised it. MT designed and supervised the study. BMH, HJH, FR, and AB collected the data and designed the figures and tables. All authors contributed to the article and approved the submitted version.
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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Summary
Keywords
bladder cancer, ncRNAs, circRNAs, expression, biomarker
Citation
Ghafouri-Fard S, Najafi S, Hussen BM, Basiri A, Hidayat HJ, Taheri M and Rashnoo F (2022) The Role of Circular RNAs in the Carcinogenesis of Bladder Cancer. Front. Oncol. 12:801842. doi: 10.3389/fonc.2022.801842
Received
25 October 2021
Accepted
28 January 2022
Published
28 February 2022
Volume
12 - 2022
Edited by
Bianca Nitzsche, Charité Universitätsmedizin Berlin, Germany
Reviewed by
Ning Li, Fourth Affiliated Hospital of China Medical University, China; Michael Höpfner, Charité Universitätsmedizin Berlin, Germany
Updates
Copyright
© 2022 Ghafouri-Fard, Najafi, Hussen, Basiri, Hidayat, Taheri and Rashnoo.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Mohammad Taheri, Mohammad_823@yahoo.com; Fariborz Rashnoo, fariborz.rashnoo@yahoo.com
This article was submitted to Genitourinary Oncology, a section of the journal Frontiers in Oncology
Disclaimer
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