Circular RNAs function as ceRNAs to regulate and control human cancer progression

Circular RNAs (circRNAs) are connected at the 3′ and 5′ ends by exon or intron cyclization, forming a complete ring structure. circRNA is more stable and conservative than linear RNA and abounds in various organisms. In recent years, increasing numbers of reports have found that circRNA plays a major role in the biological functions of a network of competing endogenous RNA (ceRNA). circRNAs can compete together with microRNAs (miRNAs) to influence the stability of target RNAs or their translation, thus, regulating gene expression at the transcriptional level. circRNAs are involved in biological processes such as tumor cell proliferation, apoptosis, invasion, and migration as ceRNAs. circRNAs, therefore, represent promising candidates for clinical diagnosis and treatment. Here, we review the progress in studying the role of circRNAs as ceRNAs in tumors and highlight the participation of circRNAs in signal transduction pathways to regulate cellular functions.

[1]  Hans Clevers,et al.  Wnt/β-Catenin Signaling and Disease , 2012, Cell.

[2]  P. Pandolfi,et al.  A ceRNA Hypothesis: The Rosetta Stone of a Hidden RNA Language? , 2011, Cell.

[3]  H. Xie,et al.  Emerging roles of circRNA_001569 targeting miR-145 in the proliferation and invasion of colorectal cancer , 2016, Oncotarget.

[4]  A. Mercurio,et al.  VEGF targets the tumour cell , 2013, Nature Reviews Cancer.

[5]  S. Hur,et al.  Antiviral Immunity and Circular RNA: No End in Sight. , 2017, Molecular cell.

[6]  Jie Chen,et al.  Circular RNA profile identifies circPVT1 as a proliferative factor and prognostic marker in gastric cancer. , 2017, Cancer letters.

[7]  Yu-ping Peng,et al.  Neuroprotection of Interleukin-6 Against NMDA-induced Neurotoxicity is Mediated by JAK/STAT3, MAPK/ERK, and PI3K/AKT Signaling Pathways , 2012, Cellular and Molecular Neurobiology.

[8]  Z. Zeng,et al.  An integrative transcriptomic analysis reveals p53 regulated miRNA, mRNA, and lncRNA networks in nasopharyngeal carcinoma , 2016, Tumor Biology.

[9]  L. Holdt,et al.  Molecular roles and function of circular RNAs in eukaryotic cells , 2017, Cellular and Molecular Life Sciences.

[10]  C. Drake,et al.  Immune checkpoint blockade: a common denominator approach to cancer therapy. , 2015, Cancer cell.

[11]  M. Lotze,et al.  High‐mobility group box 1 activates caspase‐1 and promotes hepatocellular carcinoma invasiveness and metastases , 2012, Hepatology.

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

[13]  S. Srikantan,et al.  HuR recruits let-7/RISC to repress c-Myc expression. , 2009, Genes & development.

[14]  E. Choi,et al.  Pathological roles of MAPK signaling pathways in human diseases. , 2010, Biochimica et biophysica acta.

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

[16]  Pier Paolo Pandolfi,et al.  ceRNA cross-talk in cancer: when ce-bling rivalries go awry. , 2013, Cancer discovery.

[17]  Z. Zeng,et al.  Genome-Wide Analysis of 18 Epstein-Barr Viruses Isolated from Primary Nasopharyngeal Carcinoma Biopsy Specimens , 2017, Journal of Virology.

[18]  Si Ming Man,et al.  Converging roles of caspases in inflammasome activation, cell death and innate immunity , 2015, Nature Reviews Immunology.

[19]  Suyun Huang,et al.  Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis , 2017, Journal of the National Cancer Institute.

[20]  Petar Glažar,et al.  Circular RNAs in the Mammalian Brain Are Highly Abundant, Conserved, and Dynamically Expressed. , 2015, Molecular cell.

[21]  K. Engeland Cell cycle arrest through indirect transcriptional repression by p53: I have a DREAM , 2017, Cell Death and Differentiation.

[22]  J. Xiang,et al.  miR-451 acts as a suppressor of angiogenesis in hepatocellular carcinoma by targeting the IL-6R-STAT3 pathway. , 2016, Oncology reports.

[23]  K. Helin,et al.  The E2F family: specific functions and overlapping interests , 2004, The EMBO journal.

[24]  Laising Yen,et al.  Noncoding Effects of Circular RNA CCDC66 Promote Colon Cancer Growth and Metastasis. , 2017, Cancer research.

[25]  C. Qian,et al.  Circular RNA circMTO1 acts as the sponge of microRNA‐9 to suppress hepatocellular carcinoma progression , 2017, Hepatology.

[26]  L. Dai,et al.  Competing endogenous RNA networks and gastric cancer. , 2015, World journal of gastroenterology.

[27]  P. Pandolfi,et al.  The multilayered complexity of ceRNA crosstalk and competition , 2014, Nature.

[28]  K. Nishikura,et al.  Editor meets silencer: crosstalk between RNA editing and RNA interference , 2006, Nature Reviews Molecular Cell Biology.

[29]  J. Martinou,et al.  Mitochondria in apoptosis: Bcl-2 family members and mitochondrial dynamics. , 2011, Developmental cell.

[30]  P. Heinrich,et al.  Principles of interleukin (IL)-6-type cytokine signalling and its regulation. , 2003, The Biochemical journal.

[31]  D. Bartel,et al.  Expanded identification and characterization of mammalian circular RNAs , 2014, Genome Biology.

[32]  C. Mayr,et al.  Widespread Shortening of 3′UTRs by Alternative Cleavage and Polyadenylation Activates Oncogenes in Cancer Cells , 2009, Cell.

[33]  Michael Q. Zhang,et al.  Characterization of RNase R-digested cellular RNA source that consists of lariat and circular RNAs from pre-mRNA splicing , 2006, Nucleic acids research.

[34]  Z. Zeng,et al.  Epstein-Barr virus-encoded miR-BART6-3p inhibits cancer cell metastasis and invasion by targeting long non-coding RNA LOC553103 , 2016, Cell Death and Disease.

[35]  Z. Zeng,et al.  Upregulated long non-coding RNA LINC00152 expression is associated with progression and poor prognosis of tongue squamous cell carcinoma , 2017, Journal of Cancer.

[36]  M. Zhou,et al.  Role of long non-coding RNAs in glucose metabolism in cancer , 2017, Molecular Cancer.

[37]  X. Zhang,et al.  p53 regulates mesenchymal stem cell-mediated tumor suppression in a tumor microenvironment through immune modulation , 2014, Oncogene.

[38]  Li Yang,et al.  The Biogenesis of Nascent Circular RNAs. , 2016, Cell reports.

[39]  H. You,et al.  Ape1/Ref-1 Induces Glial Cell-Derived Neurotropic Factor (GDNF) Responsiveness by Upregulating GDNF Receptor α1 Expression , 2009, Molecular and Cellular Biology.

[40]  Liangliang Yang,et al.  Silencing CDR1as inhibits colorectal cancer progression through regulating microRNA-7 , 2017, OncoTargets and therapy.

[41]  Shuzhen Wei,et al.  hsa_circ_0013958: a circular RNA and potential novel biomarker for lung adenocarcinoma , 2017, The FEBS journal.

[42]  Z. Zeng,et al.  AFAP1-AS1, a long noncoding RNA upregulated in lung cancer and promotes invasion and metastasis , 2015, Tumor Biology.

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

[44]  R. Weinberg,et al.  EMT, cell plasticity and metastasis , 2016, Cancer and Metastasis Reviews.

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

[46]  Chao Wang,et al.  Hsa_circ_0009910 promotes carcinogenesis by promoting the expression of miR-449a target IL6R in osteosarcoma. , 2018, Biochemical and biophysical research communications.

[47]  Shenmin Zhang,et al.  circRNA_100290 plays a role in oral cancer by functioning as a sponge of the miR-29 family , 2017, Oncogene.

[48]  Junming Guo,et al.  Hsa_circ_0005986 inhibits carcinogenesis by acting as a miR-129-5p sponge and is used as a novel biomarker for hepatocellular carcinoma , 2017, Oncotarget.

[49]  J. Kjems,et al.  Circular RNAs in cancer: opportunities and challenges in the field , 2017, Oncogene.

[50]  Huihuan Tang,et al.  Downregulation of microRNA-138 enhances the proliferation, migration and invasion of cholangiocarcinoma cells through the upregulation of RhoC/p-ERK/MMP-2/MMP-9. , 2013, Oncology reports.

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

[52]  Z. Zeng,et al.  The Long Noncoding RNA MALAT-1 is A Novel Biomarker in Various Cancers: A Meta-analysis Based on the GEO Database and Literature , 2016, Journal of Cancer.

[53]  M. Barbacid,et al.  Cell cycle, CDKs and cancer: a changing paradigm , 2009, Nature Reviews Cancer.

[54]  Yan Li,et al.  Circular RNA profiling reveals an abundant circHIPK3 that regulates cell growth by sponging multiple miRNAs , 2016, Nature Communications.

[55]  D. Riesner,et al.  Viroids are single-stranded covalently closed circular RNA molecules existing as highly base-paired rod-like structures. , 1976, Proceedings of the National Academy of Sciences of the United States of America.

[56]  W. Gong,et al.  TTBK2 circular RNA promotes glioma malignancy by regulating miR-217/HNF1β/Derlin-1 pathway , 2017, Journal of Hematology & Oncology.

[57]  Z. Zuo,et al.  Nickel chloride (NiCl2)-caused inflammatory responses via activation of NF-κB pathway and reduction of anti-inflammatory mediator expression in the kidney , 2015, Oncotarget.

[58]  Dong-Liang Cheng,et al.  Competing endogenous RNA interplay in cancer: mechanism, methodology, and perspectives , 2015, Tumor Biology.

[59]  Z. Zeng,et al.  Upregulated long non-coding RNA AFAP1-AS1 expression is associated with progression and poor prognosis of nasopharyngeal carcinoma , 2015, Oncotarget.

[60]  Fen Nie,et al.  The E3 Ubiquitin Ligase ITCH Negatively Regulates Canonical Wnt Signaling by Targeting Dishevelled Protein , 2012, Molecular and Cellular Biology.

[61]  P. Pandolfi,et al.  Aberrant ceRNA activity drives lung cancer , 2014, Cell Research.

[62]  Mithat Gönen,et al.  The JAK2/STAT3 signaling pathway is required for growth of CD44⁺CD24⁻ stem cell-like breast cancer cells in human tumors. , 2011, The Journal of clinical investigation.

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

[64]  S. Maas Posttranscriptional recoding by RNA editing. , 2012, Advances in protein chemistry and structural biology.

[65]  Rong Zhi,et al.  Circular RNA hsa_circ_0001982 Promotes Breast Cancer Cell Carcinogenesis Through Decreasing miR-143. , 2017, DNA and cell biology.

[66]  Li Ma,et al.  MicroRNAs and metastasis: small RNAs play big roles , 2017, Cancer and Metastasis Reviews.

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

[68]  Li Yang,et al.  Increased complexity of circRNA expression during species evolution , 2017, RNA biology.

[69]  Liangliang Xu,et al.  The circular RNA ciRS-7 (Cdr1as) acts as a risk factor of hepatic microvascular invasion in hepatocellular carcinoma , 2016, Journal of Cancer Research and Clinical Oncology.

[70]  Faryal Mehwish Awan,et al.  The Circular RNA Interacts with STAT3, Increasing Its Nuclear Translocation and Wound Repair by Modulating Dnmt3a and miR-17 Function. , 2017, Molecular therapy : the journal of the American Society of Gene Therapy.

[71]  Z. Zeng,et al.  Epstein-Barr virus encoded miR-BART11 promotes inflammation-induced carcinogenesis by targeting FOXP1 , 2016, Oncotarget.

[72]  Z. Zeng,et al.  Linking long non-coding RNAs and SWI/SNF complexes to chromatin remodeling in cancer , 2017, Molecular Cancer.

[73]  R. Zecchina,et al.  Integrated transcriptional and competitive endogenous RNA networks are cross-regulated in permissive molecular environments , 2013, Proceedings of the National Academy of Sciences.

[74]  Yixing Han,et al.  Advanced Applications of RNA Sequencing and Challenges , 2015, Bioinformatics and biology insights.

[75]  Julian Downward,et al.  Hmga2 functions as a competing endogenous RNA to promote lung cancer progression , 2013, Nature.

[76]  Minghua Wu,et al.  The Potential Role of circRNA in Tumor Immunity Regulation and Immunotherapy , 2018, Front. Immunol..

[77]  R. Cardiff Epithelial to Mesenchymal Transition Tumors: Fallacious or Snail's Pace? , 2005, Clinical Cancer Research.

[78]  J. Granados-Riverón,et al.  Does the linear Sry transcript function as a ceRNA for miR-138? The sense of antisense , 2014, F1000Research.

[79]  D. Hanahan,et al.  Hallmarks of Cancer: The Next Generation , 2011, Cell.

[80]  Rolf Backofen,et al.  DHX9 suppresses RNA processing defects originating from the Alu invasion of the human genome , 2017, Nature.

[81]  T. Slaga,et al.  GFRA1 promotes cisplatin-induced chemoresistance in osteosarcoma by inducing autophagy , 2017, Autophagy.

[82]  Yuanlin Ding,et al.  Overexpression of Circular RNA ciRS‐7 Abrogates the Tumor Suppressive Effect of miR‐7 on Gastric Cancer via PTEN/PI3K/AKT Signaling Pathway , 2018, Journal of cellular biochemistry.

[83]  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.

[84]  Wenbo Wang,et al.  Circular RNA hsa-circ-0016347 promotes proliferation, invasion and metastasis of osteosarcoma cells , 2017, Oncotarget.

[85]  Li Yang,et al.  Coordinated circRNA Biogenesis and Function with NF90/NF110 in Viral Infection. , 2017, Molecular cell.

[86]  Grace X. Y. Zheng,et al.  MicroRNAs can generate thresholds in target gene expression , 2011, Nature Genetics.

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

[88]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[89]  Z. Zeng,et al.  circGFRA1 and GFRA1 act as ceRNAs in triple negative breast cancer by regulating miR-34a , 2017, Journal of Experimental & Clinical Cancer Research.

[90]  Junxia Chen,et al.  Circular RNA MYLK as a competing endogenous RNA promotes bladder cancer progression through modulating VEGFA/VEGFR2 signaling pathway. , 2017, Cancer letters.

[91]  Z. Zeng,et al.  Long non-coding RNA AFAP1-AS1 is a novel biomarker in various cancers: a systematic review and meta-analysis based on the literature and GEO datasets , 2017, Oncotarget.

[92]  Yong Li,et al.  Circular RNAs in human cancer , 2017, Molecular Cancer.

[93]  H. Zhang,et al.  Increased circular RNA UBAP2 acts as a sponge of miR-143 to promote osteosarcoma progression , 2017, Oncotarget.

[94]  Lei Yu,et al.  The Circular RNA Cdr1as Act as an Oncogene in Hepatocellular Carcinoma through Targeting miR-7 Expression , 2016, PloS one.

[95]  P. Li,et al.  Characterization of hsa_circ_0004277 as a New Biomarker for Acute Myeloid Leukemia via Circular RNA Profile and Bioinformatics Analysis , 2017, International journal of molecular sciences.

[96]  Z. Zeng,et al.  Overexpression long non-coding RNA LINC00673 is associated with poor prognosis and promotes invasion and metastasis in tongue squamous cell carcinoma , 2016, Oncotarget.

[97]  Quanhong Sun,et al.  Circular RNA-ITCH Suppresses Lung Cancer Proliferation via Inhibiting the Wnt/β-Catenin Pathway , 2016, BioMed research international.

[98]  Chuanxin Wang,et al.  Comprehensive Circular RNA Profiling Reveals That hsa_circ_0005075, a New Circular RNA Biomarker, Is Involved in Hepatocellular Crcinoma Development , 2016, Medicine.

[99]  W. Di,et al.  MicroRNA-7 Inhibits Tumor Metastasis and Reverses Epithelial-Mesenchymal Transition through AKT/ERK1/2 Inactivation by Targeting EGFR in Epithelial Ovarian Cancer , 2014, PloS one.