Circular RNAs in cancer: an emerging key player

Circular RNAs (circRNAs) are a class of endogendous RNAs that form a covalently closed continuous loop and exist extensively in mammalian cells. Majority of circRNAs are conserved across species and often show tissue/developmental stage-specific expression. CircRNAs were first thought to be the result of splicing error; however, subsequent research shows that circRNAs can function as microRNA (miRNA) sponges and regulate splicing and transcription. Emerging evidence shows that circRNAs possess closely associated with human diseases, especially cancers, and may serve as better biomarkers. After miRNA and long noncoding RNA (lncRNA), circRNAs are becoming a new hotspot in the field of RNA of cancer. Here, we review biogenesis and metabolism of circRNAs, their functions, and potential roles in cancer.

[1]  Xuning Wang,et al.  Decreased expression of hsa_circ_001988 in colorectal cancer and its clinical significances. , 2015, International journal of clinical and experimental pathology.

[2]  Michael K. Slevin,et al.  Circular RNAs are abundant, conserved, and associated with ALU repeats. , 2013, RNA.

[3]  F. Slack,et al.  Oncomirs — microRNAs with a role in cancer , 2006, Nature Reviews Cancer.

[4]  Jiang-xia Zhao,et al.  Circular RNA is enriched and stable in exosomes: a promising biomarker for cancer diagnosis , 2015, Cell Research.

[5]  T. Gambichler,et al.  Circular RNA expression in cutaneous squamous cell carcinoma. , 2016, Journal of dermatological science.

[6]  Yunqing Li,et al.  microRNA-7 inhibits the epidermal growth factor receptor and the Akt pathway and is down-regulated in glioblastoma. , 2008, Cancer research.

[7]  Ming Yi,et al.  miRNA-7 attenuation in Schwannoma tumors stimulates growth by upregulating three oncogenic signaling pathways. , 2011, Cancer research.

[8]  Nikolaus Rajewsky,et al.  Identification and Characterization of Circular RNAs As a New Class of Putative Biomarkers in Human Blood , 2015, PloS one.

[9]  C. Cocquerelle,et al.  Mis‐splicing yields circular RNA molecules , 1993, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  Yan Li,et al.  circRNADb: A comprehensive database for human circular RNAs with protein-coding annotations , 2016, Scientific Reports.

[11]  N. Sharpless,et al.  Detecting and characterizing circular RNAs , 2014, Nature Biotechnology.

[12]  Shanshan Zhu,et al.  Circular intronic long noncoding RNAs. , 2013, Molecular cell.

[13]  Ming Liu,et al.  Circular RNA: a novel biomarker for progressive laryngeal cancer. , 2016, American journal of translational research.

[14]  Huajie Cai,et al.  cir-ITCH Plays an Inhibitory Role in Colorectal Cancer by Regulating the Wnt/β-Catenin Pathway , 2015, PloS one.

[15]  G. Shan,et al.  Exon-intron circular RNAs regulate transcription in the nucleus , 2015, Nature Structural &Molecular Biology.

[16]  Ling Tian,et al.  MicroRNA‐7 inhibits tumor growth and metastasis by targeting the phosphoinositide 3‐kinase/Akt pathway in hepatocellular carcinoma , 2012, Hepatology.

[17]  Jannetta S. Steyn,et al.  Circular RNA enrichment in platelets is a signature of transcriptome degradation. , 2016, Blood.

[18]  H. Nakaya,et al.  The Intronic Long Noncoding RNA ANRASSF1 Recruits PRC2 to the RASSF1A Promoter, Reducing the Expression of RASSF1A and Increasing Cell Proliferation , 2013, PLoS genetics.

[19]  Xiaoyan Mo,et al.  Using circular RNA as a novel type of biomarker in the screening of gastric cancer. , 2015, Clinica chimica acta; international journal of clinical chemistry.

[20]  Pieter Wesseling,et al.  RNA-Seq of Tumor-Educated Platelets Enables Blood-Based Pan-Cancer, Multiclass, and Molecular Pathway Cancer Diagnostics , 2015, Cancer cell.

[21]  Roy Parker,et al.  Circular RNAs Co-Precipitate with Extracellular Vesicles: A Possible Mechanism for circRNA Clearance , 2016, PloS one.

[22]  Junxia Chen,et al.  Screening differential circular RNA expression profiles reveals the regulatory role of circTCF25-miR-103a-3p/miR-107-CDK6 pathway in bladder carcinoma , 2016, Scientific Reports.

[23]  P. Sarnow,et al.  Initiation of protein synthesis by the eukaryotic translational apparatus on circular RNAs. , 1995, Science.

[24]  Sebastian D. Mackowiak,et al.  Circular RNAs are a large class of animal RNAs with regulatory potency , 2013, Nature.

[25]  Julia Salzman,et al.  Cell-Type Specific Features of Circular RNA Expression , 2013, PLoS genetics.

[26]  M. Ares,et al.  Circular mRNA can direct translation of extremely long repeating-sequence proteins in vivo. , 1998, RNA.

[27]  Yao-Tseng Chen,et al.  Cloning of a brain protein identified by autoantibodies from a patient with paraneoplastic cerebellar degeneration. , 1987, Proceedings of the National Academy of Sciences of the United States of America.

[28]  W. Wang,et al.  Regulation of epidermal growth factor receptor signaling by plasmid-based microRNA-7 inhibits human malignant gliomas growth and metastasis in vivo. , 2013, Neoplasma.

[29]  D. Bartel MicroRNAs Genomics, Biogenesis, Mechanism, and Function , 2004, Cell.

[30]  I. Grummt,et al.  Interaction of noncoding RNA with the rDNA promoter mediates recruitment of DNMT3b and silencing of rRNA genes. , 2010, Genes & development.

[31]  Christian Pilarsky,et al.  Glypican-1 identifies cancer exosomes and detects early pancreatic cancer , 2015, Nature.

[32]  Jun Zhang,et al.  Diverse alternative back-splicing and alternative splicing landscape of circular RNAs , 2016, Genome research.

[33]  J. Kjems,et al.  Natural RNA circles function as efficient microRNA sponges , 2013, Nature.

[34]  C. Benz,et al.  ERpS294 is a biomarker of ligand or mutational ERα activation and a breast cancer target for CDK2 inhibition. , 2017, Oncotarget.

[35]  John S Mattick,et al.  Regulation of Epidermal Growth Factor Receptor Signaling in Human Cancer Cells by MicroRNA-7* , 2009, Journal of Biological Chemistry.

[36]  Zefeng Wang Not just a sponge: new functions of circular RNAs discovered , 2015, Science China Life Sciences.

[37]  Yifeng Zhou,et al.  Circular RNA ITCH has inhibitory effect on ESCC by suppressing the Wnt/β-catenin pathway , 2015, Oncotarget.

[38]  Lei Liu,et al.  Hsa_circ_0001649: A circular RNA and potential novel biomarker for hepatocellular carcinoma. , 2016, Cancer biomarkers : section A of Disease markers.

[39]  S. Xiong,et al.  MicroRNA-7 Inhibits the Growth of Human Non-Small Cell Lung Cancer A549 Cells through Targeting BCL-2 , 2011, International journal of biological sciences.

[40]  C. Croce,et al.  MicroRNAs in Cancer. , 2009, Annual review of medicine.

[41]  Yi Shi,et al.  Desmoglein-2 is overexpressed in non-small cell lung cancer tissues and its knockdown suppresses NSCLC growth by regulation of p27 and CDK2 , 2016, Journal of Cancer Research and Clinical Oncology.

[42]  Yi Zheng,et al.  Comprehensive identification of internal structure and alternative splicing events in circular RNAs , 2016, Nature Communications.

[43]  Wei Li,et al.  The circular RNA Cdr1as, via miR-7 and its targets, regulates insulin transcription and secretion in islet cells , 2015, Scientific Reports.

[44]  P. Pandolfi,et al.  Oncogenic Role of Fusion-circRNAs Derived from Cancer-Associated Chromosomal Translocations , 2016, Cell.

[45]  Weining Yang,et al.  Foxo3 circular RNA retards cell cycle progression via forming ternary complexes with p21 and CDK2 , 2016, Nucleic acids research.

[46]  K. Ohshiro,et al.  MicroRNA-7, a homeobox D10 target, inhibits p21-activated kinase 1 and regulates its functions. , 2008, Cancer research.

[47]  Lei Cao,et al.  MicroRNA-7 regulates glioblastoma cell invasion via targeting focal adhesion kinase expression. , 2011, Chinese medical journal.

[48]  Haimin Li,et al.  Microarray expression profile of circular RNAs in human pancreatic ductal adenocarcinoma , 2015, Genomics data.

[49]  Tao Li,et al.  MicroRNA-7 functions as an anti-metastatic microRNA in gastric cancer by targeting insulin-like growth factor-1 receptor , 2013, Oncogene.

[50]  I. Hardcastle,et al.  Combined PI3K and CDK2 inhibition induces cell death and enhances in vivo antitumour activity in colorectal cancer , 2016, British Journal of Cancer.

[51]  Ashkan Golshani,et al.  Novel coding, translation, and gene expression of a replicating covalently closed circular RNA of 220 nt , 2014, Proceedings of the National Academy of Sciences.

[52]  N. Rajewsky,et al.  circRNA biogenesis competes with pre-mRNA splicing. , 2014, Molecular cell.

[53]  Kathleen R. Cho,et al.  Scrambled exons , 1991, Cell.

[54]  F. S. Foster,et al.  Foxo3 circular RNA promotes cardiac senescence by modulating multiple factors associated with stress and senescence responses , 2016, European heart journal.

[55]  Andreas W. Schreiber,et al.  The RNA Binding Protein Quaking Regulates Formation of circRNAs , 2015, Cell.

[56]  Christoph Dieterich,et al.  Analysis of intron sequences reveals hallmarks of circular RNA biogenesis in animals. , 2015, Cell reports.

[57]  Xuefei Shi,et al.  Long non-coding RNAs: a new frontier in the study of human diseases. , 2013, Cancer letters.

[58]  P. Leedman,et al.  miRNA-7-5p inhibits melanoma cell migration and invasion. , 2013, Biochemical and biophysical research communications.