Literature DB >> 28458561

Novel insights into circular RNAs in clinical application of carcinomas.

Dawei Rong1, Weiwei Tang1, Zhouxiao Li1,2, Jian Zhou3, Junfeng Shi4, Hanjin Wang1, Hongyong Cao1.   

Abstract

Circular RNAs (circRNAs), formed by nonsequential back-splicing of pre-messenger RNA (pre-mRNA) transcripts, have been widely concerned in recent years. With advances in high-throughput RNA sequencing (RNA-seq) technology, previous work has revealed that a large number of circRNAs, which are endogenous, abundant and stable in mammalian cells, may be involved in atherosclerotic vascular disease risk, neurological disorders, prion diseases and carcinomas. Remarkably, interaction between circRNAs and microRNA has already been observed to perform a significant role in a variety of cancers, including gastric cancer and colorectal cancer. Recent work has suggested that circRNAs may play critical roles in the initiation and development of cancers and could become potential new biomarkers for cancers. Herein, we review the current understanding of the roles of circRNAs in cancers and the potential implications of circRNAs in cancer-targeted therapy.

Entities:  

Keywords:  circular; diagnosis; microRNA; noncoding RNA; targeted therapy

Year:  2017        PMID: 28458561      PMCID: PMC5403007          DOI: 10.2147/OTT.S134403

Source DB:  PubMed          Journal:  Onco Targets Ther        ISSN: 1178-6930            Impact factor:   4.147


Introduction

Circular RNAs (circRNAs), a special class of endogenous noncoding RNAs, were identified in the early 1990s as transcripts and continued to be reported expressed in viruses, plants, archaea and animals.1–3 Unlike linear RNAs, which are terminated with 5′ caps and 3′ tails, circRNAs present in a circular form whose 3′ head and 5′ tail ends covalently bond together.4 Recent reports revealed that circRNAs could function as competing endogenous RNAs or microRNA sponges, regulating alternative splicing or transcription and modulating the expression of parental genes.5–7 With advances in high-throughput RNA sequencing (RNA-seq) technology, recent work has revealed that a large number of circRNAs, which are endogenous, abundant and stable in mammalian cells, may be involved in atherosclerotic vascular disease risk, neurological disorders, prion diseases and carcinomas.8–12 Remarkably, interaction between circRNAs and microRNA has already been observed to perform a significant role in a variety of cancers, including gastric cancer and colorectal cancer, which illuminates pathways to provide diagnostic or predictive biomarkers for cancers.13 For example, Sand et al confirmed a total of 322 circRNAs (143 up- and 179 downregulated) expressed in cutaneous squamous cell carcinoma, and a total of 1603 microRNA response elements (MREs) were found to be part of the differentially expressed circRNAs, which suggested that circRNAs play an important role in tumor formation by interfering with relevant microRNAs. Additionally, this study group analyzed microarray circRNA expression profiles and identified 23 upregulated and 48 downregulated circRNAs with 354 MREs in the basal cell carcinoma (BCC) as well.14 Taken together, these findings indicated that circRNAs have great potential to become new clinical diagnostic and prognostic markers and provide new insights into the treatment of carcinoma. In this review, we briefly delineate the current understanding of the roles of circRNAs and emphasize its potential implications in cancer-targeted therapy.

Categories of circRNAs

circRNAs, which form a covalently closed continuous loop, are involved in transcriptional and posttranscriptional gene expression regulation.15 circRNAs can be generated from any region of the genome, resulting in a great diversity of lengths. Like the classification system of long noncoding RNAs (lncRNAs), Qu et al classified circRNAs into five types based on their genomic proximity to the neighboring gene: 1) sense or exonic, if it originates from one or more exons of the linear transcript on the same strand; 2) intronic, if it arises from an intron of the linear transcript; 3) bidirectional or intragenic, if it is transcribed from the same gene location of the linear transcript but in close genomic proximity; 4) antisense, if it overlaps one or more exons of the linear transcript on the opposite strand; and 5) intergenic, if it is located between the genomic interval of two genes.16 Beyond this type of classification, another sort of way is established based on the mechanism.4 First, circular viral RNA genomes could be ligated to form 3′,5′- or 2′,5′-phosphodiester bonds with the involvement of host cellular enzymes. Second, circRNA midbodies can be produced during permuted transfer RNA (tRNA) biogenesis in algae and archaea or ribosomal RNA (rRNA) processing. Third, a large amount of housekeeping noncoding RNAs, such as the ribozyme RNase P, were all recognized in circular forms in archaea. Finally, abundant circRNAs may derive from spliced introns and exons.

Biological functions of circRNAs

circRNAs function as competing endogenous RNAs or microRNA sponges

circRNAs have been confirmed to function as microRNA sponges or potent competing endogenous RNA molecules, thereby influencing the posttranscriptional actions of microRNAs as suppressors of the translation in recent literature, in which the association between circRNAs and miR-7 was reported most frequently.17,18 The first microRNA sponge identified was human ciRS-7, which has been detected to be associated with cervical cancer, neuroblastoma, astrocytoma and renal cell and lung carcinoma.19 The overexpression of ciRS-7 acts as a microRNA sponge, arresting miR-7 and therefore elevating the level of miR-7 targets, which regulates the epidermal growth factor receptor (EGFR) expression that further regulates cell growth, proliferation, differentiation and signaling in human cancer cells.20 Similarly, another cir-ITCH, derived from the ITCH gene, presents a sequence enriched with three microRNA-binding sites (miR-7, miR-17 and miR-214) in esophageal squamous cell carcinoma (ESCC).21 Additionally, hsa_circ_001569 was selected as a potential regulator of colorectal cancer progression and had an interaction with miR-145.19 Therefore, the circ-miRNA axis, regardless of promotion or suppression, played an important role in cancer-related pathways and worth further study (Figure 1).
Figure 1

Mechanism of circRNAs functioning as competing endogenous RNAs or miRNA sponges.

Abbreviations: circRNAs, circular RNAs; miRNA, microRNA; mRNA, messenger RNA.

circRNAs regulate alternative splicing or transcription

Previous studies have suggested that circRNAs are competing with alternative splicing or transcription. For example, Ashwal-Fluss et al demonstrated that circMbl is generated by the second exon of the splicing factor muscleblind (MBL), which competes with canonical pre- messenger RNA (pre-mRNA) splicing. circMbl and its flanking introns contain conserved muscle blind-binding sites, which are strongly and specifically bound by MBL. Modulation of MBL levels strongly affects circMbl biosynthesis, and this effect is dependent on the MBL-binding sites.5 Therefore, this suggests that circRNAs can function in gene regulation by competing with linear splicing.

circRNAs regulate the expression of parental gene

Recent advances have revealed that circRNAs could regulate the expression of parental genes. Still taking cir-ITCH as an example, Li et al found that both cir-ITCH and the 3′-untranslated region (UTR) of ITCH share some microRNA-binding sites. Further study indicated that the interactions of cir-ITCH with miR-7, miR-17 and miR-214 might increase the level of ITCH. As a result, it could be speculated that exon-only circRNA may fulfill regulatory functions in the cytoplasm, whereas intronic circRNAs seem to be efficient for transcriptional regulation in the nucleus.21

Correlation between circRNAs and carcinomas

circRNAs have been reported to be involved in many human diseases, especially in carcinomas. Recent works have suggested that circRNAs may play important roles in the initiation and development of cancers and could potentially become new biomarkers for cancers. Up to date, the most frequently studied were that circRNAs mainly serve as microRNA sponges to regulate gene expression. MicroRNAs regulate a variety of essential biological functions such as cellular differentiation, apoptosis and proliferation and thus play a critical role in cancer progression. Based on these clues, circRNAs were found to be closely related to the development of a variety of cancers, all of which are listed in Table 1. In this review, we have listed the expression of circRNAs in various types of cancers and provide potential implications in cancer-targeted therapy (Table 1).
Table 1

Literature of circRNAs and carcinomas

Type of cancerFirst authorReceived dateJournalSequence name or more contentExpression
Cutaneous squamous cell carcinoma14Sand M2016/6/15J Dermatol SciPicking out 322 circRNAscir-143↑, cir-179↓
BCC28Sand M2016/4/21EpigenomicsScreening out 71 circRNAs23 circRNAs↑, 48 circRNAs↓
Epithelial ovarian carcinoma29Ahmed I2016/4/28OncotargetAltered expression patternUnclear
Ovarian carcinoma30Bachmayr-Heyda A2016/5/14OncotargetUnclearUnclear
Cervical cancer31Abdelmohsen K2017/1/13RNA BiolCircPABPN1 (hsa_circ_0031288)Unclear
Laryngeal cancer27Xuan L2016/5/10Am J Transl Reshsa_circ_104912, hsa_circ_100855hsa_circ_104912↓, hsa_circ_100855↑
Hepatoma carcinoma32Qin M2015/11/26Cancer Biomarkhsa_circ_0001649hsa_circ_0001649↓
Hepatoma carcinoma24Yu L2016/7/9PLoS OnecircRNA Cdr1circRNA Cdr1↑
Hepatoma carcinoma25Shang X2016/6/4Medicine (Baltimore)hsa_circ_0000520, hsa_circ_0005075, hsa_circ_0066444Unclear
Hepatoma carcinoma33Xu L2016/9/12J Cancer Res Clin OncolciRS-7 (Cdr1as)ciRS-7 (Cdr1as)↓
Pancreatic ductal carcinoma34Qu S2015/10/21Genom DataMicroarray expression profileUnclear
Neuroglioma35Song X2016/2/14Nucleic Acids ResScreening out 476 circRNAsUnclear
Neuroglioma36Barbagallo D2015/12/20OncotargetUnclearUnclear
Neuroglioma37Yang P2016/9/11OncotargetcZNF292 circRNAcZNF292 circRNA↓
Colorectal cancer38Wang X2016/2/18Int J Clin Exp Patholhsa_circ_001988hsa_circ_001988↓
Colorectal cancer, ovarian carcinoma39Bachmayr-Heyda A2015/1/28Sci RepThe percent of circ/lineThe percent of circ/line↓
Colorectal cancer12Xie H2016/4/9Oncotargethsa_circ_001569hsa_circ_001569↑
Colorectal cancer40Huang G2015/6/26PLoS Onecir-ITCHcir-ITCH↓
Colorectal cancer41Zhu M2017/1/20Biomed Pharmacothercirc-BANPcirc-BANP↑
KRAS mutant colon cancer42Dou Y2016/11/29Sci RepcircRNAcircRNA↓
Gastric carcinoma22Li P2015/2/18Clin Chim Actahsa_circ_002059hsa_circ_002059↓
Gastric carcinoma43Li P2017/1/13Br J Cancerhsa_circ_0000096hsa_circ_0000096↓
Gastric carcinoma44Chen S2017/1/29Clin Chim Actahsa_circ_0000190hsa_circ_0000190↓
Esophageal carcinoma12Xia W2016/10/19Sci Rephsa_circ_0067934hsa_circ_0067934↑
Radio-resistant esophageal cancer45Su H2016/7/29J Transl Medhsa_circ_001059, hsa_circ_100385, hsa_circ_104983, hsa_circ_000167, hsa_circ_101877, hsa_circ_102913, hsa_circ_000695hsa_circ_001059↑, hsa_circ_100385↑, hsa_circ_104983↑, hsa_circ_000167↓, hsa_circ_101877↓, hsa_circ_102913↓, hsa_circ_000695↓
Esophageal carcinoma21Li F2015/3/10Oncotargetcir-ITCHcir-ITCH↓
Hematopoiesis malignancies46Bonizzato A2016/10/16Blood Cancer JScreening out the expression of circRNAsUnclear
Bladder carcinoma26Zhong Z2016/8/4Sci RepcircTCF25circTCF25↑
Bladder carcinoma47Huang M2016/7/1OncotargetcircRNA M, YLKUnclear
Clear cell renal cell carcinoma48Wang K2017/1/17Cancer LettcircHIAT1circHIAT1↓
Breast cancer49Yang W2015/12/15OncogeneFoxo3 circRNAFoxo3 circRNA↑
Breast cancer50Nair AA2016/11/10OncotargetUnclearUnclear
Lung cancer23Wan L2016/9/20Biomed Res IntcircRNA-ITCHcircRNA-ITCH↓
Seven cancers51Zheng Q2016/4/7Nat CommuncircHIPK3circHIPK3↓
Cancer52Du WW2016/2/11Nucleic Acids Rescirc-Foxo3circ-Foxo3↓
Cancer53Hansen TB2011/10/4EMBO JCDR1Unclear
Carcinoma54Du WW2016/11/26Cell Death Differcirc-Foxo3circ-Foxo3↓

Notes: ↓ means downregulated. ↑ means upregulated.

Abbreviations: circRNAs, circular RNA; BCC, basal cell carcinoma.

Previous studies revealed that circRNAs showed large capabilities in gene regulation by playing microRNA sponge effects. Some circRNAs present as a downward trend to regulate the pathways. For instance, hsa_circ_002059, a typical circRNA, was first found to be significantly down-regulated in gastric cancer tissues compared with paired adjacent nontumor tissues, and further research found that lower expression levels of hsa_circ_002059 in plasma were significantly correlated with distal metastasis, tumor–node– metastasis (TNM) stage, gender and age, which might be a potential novel and stable biomarker for the diagnosis of gastric carcinoma.22 In a study of lung cancer, the expression of cir-ITCH was significantly decreased in lung cancer tissues. Ectopic expression of cir-ITCH markedly elevated its parental cancer-suppressive gene, ITCH, expression and inhibited proliferation of lung cancer cells.23 Altogether, these findings suggested that circRNAs may play an inhibitory role in some cancer progression by enhancing its parental gene expression. However, not all circRNAs play a downward regulation in cancer progress. Yu et al demonstrated that Cdr1as expression was upregulated in hepatocellular carcinoma (HCC) tissues compared with the adjacent nontumor tissues. Moreover, overexpression of miR-7 could suppress the direct target gene CCNE1 and PIK3CD expression. Knockdown of Cdr1as suppressed the expression of miR-7 and also inhibited the CCNE1 and PIK3CD expression. Furthermore, knockdown of Cdr1as suppressed the HCC cell proliferation and invasion through targeting miR-7, suggesting that Cdr1as acted as an oncogene partly through targeting miR-7 in HCC.24 Shang et al also did a study of circRNAs in HCC and reported that three circRNAs played roles (hsa_circ_0000520, hsa_circ_0005075 and hsa_circ_0066444) in HCC and only hsa_circ_0005075 exhibited significant difference in expression between HCC and normal tissues. The hsa_circ_0005075 expression correlated with HCC tumor size and showed good diagnostic potential.25 Subsequently, Zhong et al used microarray assay to screen circRNA expression profiles of bladder carcinoma and predicted that circTCF25 could downregulate miR-103a-3p and miR-107, increase CDK6 expression and promote proliferation and migration in vitro and in vivo, suggesting that circTCF25 might be a new promising marker for bladder cancer.26 Intriguingly and strikingly, Xuan et al investigated the expression of circRNAs in four paired laryngeal squamous cell cancer (LSCC) tissues and adjacent nontumor tissues by microarray analysis. The results showed significant upregulation (n=302) or downregulation (n=396) of 698 circRNAs in LSCC tissues. They further detected hsa_circ_100855 as the most upregulated circRNA and hsa_circ_104912 as the most downregulated circRNA using quantitative real-time-PCR methods. Additionally, patients with T3–4 stages, neck nodal metastasis or advanced clinical stage had higher hsa_circ_100855 expression, and patients with T3–4 stages, neck nodal metastasis, poor differentiation or advanced clinical stage had a lower hsa_circ_104912 expression. Overall, their data suggest that circRNAs play an important role in the tumorigenesis of LSCC and may serve as novel and stable biomarkers for the diagnosis and progression of LSCC.27 Sand et al identified 23 upregulated and 48 downregulated circRNAs with 354 MREs capable of sequestering microRNA target sequences of the BCC miRNome through microarray circRNA expression profiles and described a variety of circRNAs that are potentially involved in the molecular pathogenesis of BCC.28

Conclusion and perspective

In the past, circRNAs were considered impossible to play a key role in the biological process because they were thought to be a byproduct of aberrant splicing events or intermediates that had escaped from intron lariat debranching. Thanks to the advancements in high-throughput sequencing technologies and bioinformatics, circRNAs were found to be broadly expressed and perform regulation in atherosclerotic vascular disease, neurological disorders, prion diseases and carcinomas. In summary, functional roles of circRNAs in the regulation of protein-coding gene expression through acting as microRNA sponges, regulating alternative splicing or transcription and modulating the expression of parental genes confer a great variety of functional potential to circRNAs. The fact that circRNAs are found abundant in clinical blood or tissue samples makes circRNA a promising diagnostic biomarker for cancer screening and prognostic evaluation. Although the number of circRNAs with known functions is expanding, there are still thousands of circRNAs whose functions remain unknown. A deeper understanding of circRNA biogenesis may be needed to shed light on the road of functional consequences of circRNA.
  53 in total

1.  Scrambled exons.

Authors:  J M Nigro; K R Cho; E R Fearon; S E Kern; J M Ruppert; J D Oliner; K W Kinzler; B Vogelstein
Journal:  Cell       Date:  1991-02-08       Impact factor: 41.582

2.  Circular RNA: a novel biomarker for progressive laryngeal cancer.

Authors:  Lijia Xuan; Lingmei Qu; Han Zhou; Peng Wang; Haoyang Yu; Tianyi Wu; Xin Wang; Qiuying Li; Linli Tian; Ming Liu; Yanan Sun
Journal:  Am J Transl Res       Date:  2016-02-15       Impact factor: 4.060

3.  Circular RNA ciRS-7-A Promising Prognostic Biomarker and a Potential Therapeutic Target in Colorectal Cancer.

Authors:  Wenhao Weng; Qing Wei; Shusuke Toden; Kazuhiro Yoshida; Takeshi Nagasaka; Toshiyoshi Fujiwara; Sanjun Cai; Huanlong Qin; Yanlei Ma; Ajay Goel
Journal:  Clin Cancer Res       Date:  2017-02-07       Impact factor: 12.531

4.  Decreased expression of hsa_circ_001988 in colorectal cancer and its clinical significances.

Authors:  Xuning Wang; Yue Zhang; Liang Huang; Jiajin Zhang; Fei Pan; Bing Li; Yongfeng Yan; Baoqing Jia; Hongyi Liu; Shiyou Li; Wei Zheng
Journal:  Int J Clin Exp Pathol       Date:  2015-12-01

5.  Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs.

Authors:  Qiupeng Zheng; Chunyang Bao; Weijie Guo; Shuyi Li; Jie Chen; Bing Chen; Yanting Luo; Dongbin Lyu; Yan Li; Guohai Shi; Linhui Liang; Jianren Gu; Xianghuo He; Shenglin Huang
Journal:  Nat Commun       Date:  2016-04-06       Impact factor: 14.919

Review 6.  CircRNAs in hematopoiesis and hematological malignancies.

Authors:  A Bonizzato; E Gaffo; G Te Kronnie; S Bortoluzzi
Journal:  Blood Cancer J       Date:  2016-10-14       Impact factor: 11.037

7.  Circular RNA-ITCH Suppresses Lung Cancer Proliferation via Inhibiting the Wnt/β-Catenin Pathway.

Authors:  Li Wan; Lin Zhang; Kai Fan; Zai-Xing Cheng; Quan-Chao Sun; Jian-Jun Wang
Journal:  Biomed Res Int       Date:  2016-08-24       Impact factor: 3.411

8.  Comprehensive Circular RNA Profiling Reveals That hsa_circ_0005075, a New Circular RNA Biomarker, Is Involved in Hepatocellular Crcinoma Development.

Authors:  Xingchen Shang; Guanzhen Li; Hui Liu; Tao Li; Juan Liu; Qi Zhao; Chuanxi Wang
Journal:  Medicine (Baltimore)       Date:  2016-05       Impact factor: 1.889

9.  Circular RNAs and their associations with breast cancer subtypes.

Authors:  Asha A Nair; Nifang Niu; Xiaojia Tang; Kevin J Thompson; Liewei Wang; Jean-Pierre Kocher; Subbaya Subramanian; Krishna R Kalari
Journal:  Oncotarget       Date:  2016-12-06

10.  Silencing of cZNF292 circular RNA suppresses human glioma tube formation via the Wnt/β-catenin signaling pathway.

Authors:  Ping Yang; Zhijun Qiu; Yuan Jiang; Lei Dong; Wensheng Yang; Chao Gu; Guang Li; Yu Zhu
Journal:  Oncotarget       Date:  2016-09-27
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  27 in total

1.  Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKα signaling in STK11 mutant lung cancer.

Authors:  Xiuyuan Chen; Rui Mao; Wenmei Su; Xia Yang; Qianqian Geng; Chunfang Guo; Zhuwen Wang; Jun Wang; Laura A Kresty; David G Beer; Andrew C Chang; Guoan Chen
Journal:  Autophagy       Date:  2019-06-28       Impact factor: 16.016

2.  Screening of up- and downregulation of circRNAs in HBV-related hepatocellular carcinoma by microarray.

Authors:  Shichang Cui; Zhiling Qian; Yuhan Chen; Lei Li; Peng Li; Huiguo Ding
Journal:  Oncol Lett       Date:  2017-10-25       Impact factor: 2.967

3.  Circ_0091579 Serves as a Tumor-Promoting Factor in Hepatocellular Carcinoma Through miR-1225-5p/PLCB1 Axis.

Authors:  Di Zhang; Yu Zhang; Xiwu Zhang; Hongjun Zhai; Xiaoli Sun; Yiming Li
Journal:  Dig Dis Sci       Date:  2021-02-08       Impact factor: 3.199

4.  Upregulation of circ_0066444 promotes the proliferation, invasion, and migration of gastric cancer cells.

Authors:  Dawei Rong; Chaoxi Dong; Kai Fu; Hanjin Wang; Weiwei Tang; Hongyong Cao
Journal:  Onco Targets Ther       Date:  2018-05-11       Impact factor: 4.147

5.  Clinical Significance of the Decreased Expression of hsa_circ_001242 in Oral Squamous Cell Carcinoma.

Authors:  Shuai Sun; Bowen Li; Yufan Wang; Xiang Li; Panpan Wang; Feng Wang; Wei Zhang; Hongyu Yang
Journal:  Dis Markers       Date:  2018-07-04       Impact factor: 3.434

Review 6.  Circular RNAs: a new frontier for cancer diagnosis and therapy.

Authors:  Miaoci Zhang; Yan Xin
Journal:  J Hematol Oncol       Date:  2018-02-13       Impact factor: 17.388

7.  Novel circular RNA expression profile of uveal melanoma revealed by microarray.

Authors:  Xuan Yang; Yang Li; Yueming Liu; Xiaolin Xu; Yingzhi Wang; Yanni Yan; Wenjia Zhou; Jingyan Yang; Wenbin Wei
Journal:  Chin J Cancer Res       Date:  2018-12       Impact factor: 5.087

Review 8.  Circular RNAs: clinical relevance in cancer.

Authors:  Zhijie Xu; Yuanliang Yan; Shuangshuang Zeng; Shuang Dai; Xi Chen; Jie Wei; Zhicheng Gong
Journal:  Oncotarget       Date:  2017-12-01

9.  Screening circular RNA expression patterns following focal cerebral ischemia in mice.

Authors:  Cuiying Liu; Chencheng Zhang; Jian Yang; Xiaokun Geng; Huishan Du; Xunming Ji; Heng Zhao
Journal:  Oncotarget       Date:  2017-09-23

10.  Identification and comparison of novel circular RNAs with associated co-expression and competing endogenous RNA networks in pulmonary tuberculosis.

Authors:  Xing Zhang; Min Zhu; Rong Yang; Weifeng Zhao; Xiaolong Hu; Jianhe Gan
Journal:  Oncotarget       Date:  2017-11-27
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