The Emerging Function and Mechanism of ceRNAs in Cancer.

Complex diseases, such as cancer, are often associated with aberrant gene expression at both the transcriptional and post-transcriptional level. Over the past several years, competing endogenous RNAs (ceRNAs) have emerged as an important class of post-transcriptional regulators that alter gene expression through a miRNA-mediated mechanism. Recent studies in both solid tumors and hematopoietic malignancies showed that ceRNAs have significant roles in cancer pathogenesis by altering the expression of key tumorigenic or tumor-suppressive genes. Characterizing the identity, function, and mechanism of the ceRNAs will not only further our fundamental understanding of RNA-mediated cancer pathogenesis, but may also shed light on the development of new RNA-based therapeutic strategies for treating cancer.

[1]  T. Xia,et al.  Long noncoding RNA associated-competing endogenous RNAs in gastric cancer , 2014, Scientific Reports.

[2]  I. Irminger-Finger,et al.  Long non-coding RNA and microRNAs might act in regulating the expression of BARD1 mRNAs. , 2014, The international journal of biochemistry & cell biology.

[3]  M. Mann,et al.  Stable Isotope Labeling by Amino Acids in Cell Culture, SILAC, as a Simple and Accurate Approach to Expression Proteomics* , 2002, Molecular & Cellular Proteomics.

[4]  Tao Xi,et al.  The 3′UTR of the pseudogene CYP4Z2P promotes tumor angiogenesis in breast cancer by acting as a ceRNA for CYP4Z1 , 2015, Breast Cancer Research and Treatment.

[5]  Frances M. G. Pearl,et al.  Conserved Regulation of Cardiac Calcium Uptake by Peptides Encoded in Small Open Reading Frames , 2013, Science.

[6]  Bernhard Kuster,et al.  Quantitative mass spectrometry in proteomics: critical review update from 2007 to the present , 2012, Analytical and Bioanalytical Chemistry.

[7]  Ferdinando Di Cunto,et al.  Coding-Independent Regulation of the Tumor Suppressor PTEN by Competing Endogenous mRNAs , 2011, Cell.

[8]  R. Weinberg,et al.  A Pleiotropically Acting Microrna, Mir-31, Inhibits Breast Cancer Metastasis Accessed Terms of Use Detailed Terms a Pleiotropically Acting Microrna, Mir-31, Inhibits Breast Cancer Metastasis , 2022 .

[9]  Phillip A. Sharp,et al.  Emerging Roles for Natural MicroRNA Sponges , 2010, Current Biology.

[10]  M. Ferracin,et al.  miR-125b targets erythropoietin and its receptor and their expression correlates with metastatic potential and ERBB2/HER2 expression , 2013, Molecular Cancer.

[11]  F. Liu,et al.  A long noncoding RNA activated by TGF-β promotes the invasion-metastasis cascade in hepatocellular carcinoma. , 2014, Cancer cell.

[12]  D. Bartel,et al.  MicroRNA-Directed Cleavage of HOXB8 mRNA , 2004, Science.

[13]  R. Aebersold,et al.  Applying mass spectrometry-based proteomics to genetics, genomics and network biology , 2009, Nature Reviews Genetics.

[14]  Scott B. Dewell,et al.  Transcriptome-wide Identification of RNA-Binding Protein and MicroRNA Target Sites by PAR-CLIP , 2010, Cell.

[15]  Jianwen Liu,et al.  Post‐transcriptional regulation of the tumor suppressor miR‐139‐5p and a network of miR‐139‐5p‐mediated mRNA interactions in colorectal cancer , 2014, The FEBS journal.

[16]  Ming Sun,et al.  Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer , 2014, Molecular Cancer.

[17]  Shiaw-Min Hwang,et al.  Suppression of hepatocellular carcinoma by baculovirus-mediated expression of long non-coding RNA PTENP1 and MicroRNA regulation. , 2015, Biomaterials.

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

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

[20]  Nikolaus Rajewsky,et al.  Competition between target sites of regulators shapes post-transcriptional gene regulation , 2014, Nature Reviews Genetics.

[21]  Annick Harel-Bellan,et al.  Tandem affinity purification of miRNA target mRNAs (TAP-Tar) , 2009, Nucleic acids research.

[22]  G. Storz,et al.  GadY, a Small-RNA Regulator of Acid Response Genes in Escherichia coli , 2004, Journal of bacteriology.

[23]  S. Gygi,et al.  Quantitative analysis of complex protein mixtures using isotope-coded affinity tags , 1999, Nature Biotechnology.

[24]  Luigi Naldini,et al.  Stable knockdown of microRNA in vivo by lentiviral vectors , 2009, Nature Methods.

[25]  A. Chinnaiyan,et al.  The Long Non-Coding RNA PCAT-1 Promotes Prostate Cancer Cell Proliferation through cMyc12 , 2014, Neoplasia.

[26]  J. Rinn,et al.  Localization and abundance analysis of human lncRNAs at single-cell and single-molecule resolution , 2015, Genome Biology.

[27]  Shi-bin Yang,et al.  Long noncoding RNA CCAT1 promotes hepatocellular carcinoma progression by functioning as let-7 sponge , 2015, Journal of experimental & clinical cancer research : CR.

[28]  Feng Zhang,et al.  A novel biomarker Linc00974 interacting with KRT19 promotes proliferation and metastasis in hepatocellular carcinoma , 2014, Cell Death and Disease.

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

[30]  Richard Bonneau,et al.  The mRNA-bound proteome and its global occupancy profile on protein-coding transcripts. , 2012, Molecular cell.

[31]  Xuerui Yang,et al.  An Extensive MicroRNA-Mediated Network of RNA-RNA Interactions Regulates Established Oncogenic Pathways in Glioblastoma , 2011, Cell.

[32]  J. Rinn,et al.  Ribosome profiling reveals resemblance between long non-coding RNAs and 5′ leaders of coding RNAs , 2013, Development.

[33]  Hervé Seitz,et al.  Redefining MicroRNA Targets , 2009, Current Biology.

[34]  X. Wang,et al.  A long noncoding RNA critically regulates Bcr-Abl-mediated cellular transformation by acting as a competitive endogenous RNA , 2014, Oncogene.

[35]  Jeroen Krijgsveld,et al.  System-wide identification of RNA-binding proteins by interactome capture , 2013, Nature Protocols.

[36]  Pradeep S Rajendran,et al.  Single-cell dissection of transcriptional heterogeneity in human colon tumors , 2011, Nature Biotechnology.

[37]  Norman E. Davey,et al.  Insights into RNA Biology from an Atlas of Mammalian mRNA-Binding Proteins , 2012, Cell.

[38]  Y. Mo,et al.  Negative regulation of lncRNA GAS5 by miR-21 , 2013, Cell Death and Differentiation.

[39]  Yu-qin Pan,et al.  Upregulated lncRNA-UCA1 contributes to progression of hepatocellular carcinoma through inhibition of miR-216b and activation of FGFR1/ERK signaling pathway , 2015, Oncotarget.

[40]  Jie Xu,et al.  Long noncoding RNA GAPLINC regulates CD44-dependent cell invasiveness and associates with poor prognosis of gastric cancer. , 2014, Cancer research.

[41]  I. Oglesby,et al.  Isolation and identification of cell-specific microRNAs targeting a messenger RNA using a biotinylated anti-sense oligonucleotide capture affinity technique , 2013, Nucleic acids research.

[42]  Jørgen Kjems,et al.  miRNA‐dependent gene silencing involving Ago2‐mediated cleavage of a circular antisense RNA , 2011, The EMBO journal.

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

[44]  I. Ng,et al.  Long non‐coding RNA HOTTIP is frequently up‐regulated in hepatocellular carcinoma and is targeted by tumour suppressive miR‐125b , 2015, Liver international : official journal of the International Association for the Study of the Liver.

[45]  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.

[46]  Tao Xi,et al.  FOXO1 3′UTR functions as a ceRNA in repressing the metastases of breast cancer cells via regulating miRNA activity , 2014, FEBS letters.

[47]  Jay Shendure,et al.  Transcriptome-wide miR-155 binding map reveals widespread noncanonical microRNA targeting. , 2012, Molecular cell.

[48]  B. Reinhart,et al.  Prediction of Plant MicroRNA Targets , 2002, Cell.

[49]  A. Chinnaiyan,et al.  The emergence of lncRNAs in cancer biology. , 2011, Cancer discovery.

[50]  L. Castellano,et al.  Emerging Roles of Competing Endogenous RNAs in Cancer: Insights from the Regulation of PTEN , 2013, Molecular and Cellular Biology.

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

[52]  Weining Yang,et al.  Versican 3′‐untranslated region (3′‐UTR) functions as a ceRNA in inducing the development of hepatocellular carcinoma by regulating miRNA activity , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[53]  Nadav S. Bar,et al.  Landscape of transcription in human cells , 2012, Nature.

[54]  Michael Q. Zhang,et al.  Model-guided quantitative analysis of microRNA-mediated regulation on competing endogenous RNAs using a synthetic gene circuit , 2015, Proceedings of the National Academy of Sciences.

[55]  Andrew H. Thompson,et al.  Tandem mass tags: a novel quantification strategy for comparative analysis of complex protein mixtures by MS/MS. , 2003, Analytical chemistry.

[56]  Margaret S. Ebert,et al.  MicroRNA sponges: competitive inhibitors of small RNAs in mammalian cells , 2007, Nature Methods.

[57]  Thomas M. Keane,et al.  The BRAF Pseudogene Functions as a Competitive Endogenous RNA and Induces Lymphoma In Vivo , 2015, Cell.

[58]  Yue Wang,et al.  Endogenous miRNA sponge lincRNA-RoR regulates Oct4, Nanog, and Sox2 in human embryonic stem cell self-renewal. , 2013, Developmental cell.

[59]  Qun Zhou,et al.  lincRNA-RoR and miR-145 Regulate Invasion in Triple-Negative Breast Cancer via Targeting ARF6 , 2014, Molecular Cancer Research.

[60]  Yvonne Tay,et al.  MicroRNAs to Nanog, Oct4 and Sox2 coding regions modulate embryonic stem cell differentiation , 2008, Nature.

[61]  P. Pandolfi,et al.  In Vivo Identification of Tumor- Suppressive PTEN ceRNAs in an Oncogenic BRAF-Induced Mouse Model of Melanoma , 2011, Cell.

[62]  C. Croce,et al.  MicroRNA-133 controls cardiac hypertrophy , 2007, Nature Medicine.

[63]  J. Rinn,et al.  Modular regulatory principles of large non-coding RNAs , 2012, Nature.

[64]  Phillip A Sharp,et al.  Endogenous miRNA and target concentrations determine susceptibility to potential ceRNA competition. , 2014, Molecular cell.

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

[66]  J. Rinn,et al.  Discovery and annotation of long noncoding RNAs , 2015, Nature Structural &Molecular Biology.

[67]  David Tollervey,et al.  Cross-linking, ligation, and sequencing of hybrids reveals RNA–RNA interactions in yeast , 2011, Proceedings of the National Academy of Sciences.

[68]  Hui Sun,et al.  OCT4B modulates OCT4A expression as ceRNA in tumor cells. , 2015, Oncology reports.

[69]  Yvonne Tay,et al.  A Pattern-Based Method for the Identification of MicroRNA Binding Sites and Their Corresponding Heteroduplexes , 2006, Cell.

[70]  C. Thornton,et al.  RNA-dominant diseases. , 2006, Human molecular genetics.

[71]  J. Ule,et al.  iCLIP reveals the function of hnRNP particles in splicing at individual nucleotide resolution , 2010, Nature Structural &Molecular Biology.

[72]  Phillipe Loher,et al.  Argonaute CLIP-Seq reveals miRNA targetome diversity across tissue types , 2014, Scientific Reports.

[73]  Ling-Ling Chen,et al.  Complementary Sequence-Mediated Exon Circularization , 2014, Cell.

[74]  Stefan Hüttelmaier,et al.  Rapid identification of regulatory microRNAs by miTRAP (miRNA trapping by RNA in vitro affinity purification) , 2014, Nucleic acids research.

[75]  A. Hatzigeorgiou,et al.  Redirection of Silencing Targets by Adenosine-to-Inosine Editing of miRNAs , 2007, Science.

[76]  Myriam Gorospe,et al.  MS2-TRAP (MS2-tagged RNA affinity purification): tagging RNA to identify associated miRNAs. , 2012, Methods.

[77]  Weining Yang,et al.  The pseudogene TUSC2P promotes TUSC2 function by binding multiple microRNAs , 2014, Nature Communications.

[78]  Phillip A Sharp,et al.  MicroRNA sponges: progress and possibilities. , 2010, RNA.

[79]  Kotb Abdelmohsen,et al.  LincRNA-p21 suppresses target mRNA translation. , 2012, Molecular cell.

[80]  Yaou Zhang,et al.  Expression of Versican 3′-Untranslated Region Modulates Endogenous MicroRNA Functions , 2010, PloS one.

[81]  Zhiming Wang,et al.  A long non-coding RNA, PTCSC3, as a tumor suppressor and a target of miRNAs in thyroid cancer cells , 2013, Experimental and therapeutic medicine.

[82]  H. Tsai,et al.  Labeled microRNA pull-down assay system: an experimental approach for high-throughput identification of microRNA-target mRNAs , 2009, Nucleic acids research.

[83]  George M. Church,et al.  Highly Multiplexed Subcellular RNA Sequencing in Situ , 2014, Science.

[84]  Jiayi Wang,et al.  CREB up-regulates long non-coding RNA, HULC expression through interaction with microRNA-372 in liver cancer , 2010, Nucleic acids research.

[85]  T. Hwa,et al.  Quantitative Characteristics of Gene Regulation by Small RNA , 2007, PLoS Biology.

[86]  Anton J. Enright,et al.  Human MicroRNA Targets , 2004, PLoS biology.

[87]  X. Zhuang,et al.  Spatially resolved, highly multiplexed RNA profiling in single cells , 2015, Science.

[88]  J. Rinn,et al.  Integrative analyses reveal a long noncoding RNA-mediated sponge regulatory network in prostate cancer , 2016, Nature Communications.

[89]  Yan Zhang,et al.  Long non-coding RNA CCAT1 promotes gallbladder cancer development via negative modulation of miRNA-218-5p , 2015, Cell Death and Disease.

[90]  Tao Xi,et al.  AEG-1 3'-untranslated region functions as a ceRNA in inducing epithelial-mesenchymal transition of human non-small cell lung cancer by regulating miR-30a activity. , 2015, European journal of cell biology.

[91]  Howard Y. Chang,et al.  Genome regulation by long noncoding RNAs. , 2012, Annual review of biochemistry.

[92]  Michael Kertesz,et al.  The role of site accessibility in microRNA target recognition , 2007, Nature Genetics.

[93]  K. Gunsalus,et al.  Combinatorial microRNA target predictions , 2005, Nature Genetics.

[94]  M. Todesco,et al.  Target mimicry provides a new mechanism for regulation of microRNA activity , 2007, Nature Genetics.

[95]  Howard Y. Chang,et al.  Dissecting noncoding and pathogen RNA–protein interactomes , 2015, RNA.

[96]  A. Mele,et al.  Ago HITS-CLIP decodes miRNA-mRNA interaction maps , 2009, Nature.

[97]  A. Mele,et al.  Hepatitis C Virus RNA Functionally Sequesters miR-122 , 2015, Cell.

[98]  Florian Caiment,et al.  RNAi-Mediated Allelic trans-Interaction at the Imprinted Rtl1/Peg11 Locus , 2005, Current Biology.

[99]  Tyson A. Clark,et al.  HITS-CLIP yields genome-wide insights into brain alternative RNA processing , 2008, Nature.

[100]  Luigi Naldini,et al.  Endogenous microRNA can be broadly exploited to regulate transgene expression according to tissue, lineage and differentiation state , 2007, Nature Biotechnology.

[101]  M. Zavolan,et al.  Analysis of CDS-located miRNA target sites suggests that they can effectively inhibit translation , 2013, Genome research.

[102]  D. Cacchiarelli,et al.  A Long Noncoding RNA Controls Muscle Differentiation by Functioning as a Competing Endogenous RNA , 2011, Cell.

[103]  R. Sandberg,et al.  Full-Length mRNA-Seq from single cell levels of RNA and individual circulating tumor cells , 2012, Nature Biotechnology.

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

[105]  A. Lund,et al.  Isolation of microRNA targets using biotinylated synthetic microRNAs. , 2007, Methods.

[106]  C. Burge,et al.  Most mammalian mRNAs are conserved targets of microRNAs. , 2008, Genome research.

[107]  John M. Shelton,et al.  A Micropeptide Encoded by a Putative Long Noncoding RNA Regulates Muscle Performance , 2015, Cell.

[108]  D. Tollervey,et al.  Mapping the Human miRNA Interactome by CLASH Reveals Frequent Noncanonical Binding , 2013, Cell.

[109]  Hui Zhou,et al.  starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein–RNA interaction networks from large-scale CLIP-Seq data , 2013, Nucleic Acids Res..

[110]  Shuhan Sun,et al.  Long noncoding RNA DANCR increases stemness features of hepatocellular carcinoma by derepression of CTNNB1 , 2016, Hepatology.

[111]  Dongming Liang,et al.  Short intronic repeat sequences facilitate circular RNA production , 2014, Genes & development.

[112]  Zipora Y. Fligelman,et al.  Systematic identification of abundant A-to-I editing sites in the human transcriptome , 2004, Nature Biotechnology.

[113]  Prahlad T. Ram,et al.  Cupid: simultaneous reconstruction of microRNA-target and ceRNA networks , 2015, Genome research.

[114]  J. Steitz,et al.  Down-Regulation of a Host MicroRNA by a Herpesvirus saimiri Noncoding RNA , 2010, Science.

[115]  P. Pandolfi,et al.  A coding-independent function of gene and pseudogene mRNAs regulates tumour biology , 2010, Nature.

[116]  Zhuo Xi,et al.  Knockdown of long non-coding RNA XIST exerts tumor-suppressive functions in human glioblastoma stem cells by up-regulating miR-152. , 2015, Cancer letters.

[117]  M. Mann,et al.  Quantitative, high-resolution proteomics for data-driven systems biology. , 2011, Annual review of biochemistry.

[118]  D. Bartel MicroRNAs: Target Recognition and Regulatory Functions , 2009, Cell.

[119]  Yi Xing,et al.  Adenosine deamination in human transcripts generates novel microRNA binding sites , 2009, Human molecular genetics.

[120]  Wei Li,et al.  Dynamic analyses of alternative polyadenylation from RNA-seq reveal a 3′-UTR landscape across seven tumour types , 2014, Nature Communications.

[121]  Vikram Agarwal,et al.  Assessing the ceRNA hypothesis with quantitative measurements of miRNA and target abundance. , 2014, Molecular cell.

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

[123]  Xiaoping Zhou,et al.  Linc-RNA-RoR acts as a "sponge" against mediation of the differentiation of endometrial cancer stem cells by microRNA-145. , 2014, Gynecologic oncology.

[124]  Qihong Huang,et al.  Pseudogene PTENP1 Functions as a Competing Endogenous RNA to Suppress Clear-Cell Renal Cell Carcinoma Progression , 2014, Molecular Cancer Therapeutics.

[125]  C. Burge,et al.  Conserved Seed Pairing, Often Flanked by Adenosines, Indicates that Thousands of Human Genes are MicroRNA Targets , 2005, Cell.

[126]  J. Vogel,et al.  Identification of regulatory RNAs in Bacillus subtilis , 2010, Nucleic acids research.

[127]  S. Dima,et al.  Pseudogene INTS6P1 regulates its cognate gene INTS6 through competitive binding of miR-17-5p in hepatocellular carcinoma , 2015, Oncotarget.

[128]  P. A. Futreal,et al.  Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. , 2012, The New England journal of medicine.

[129]  Charles Gawad,et al.  Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types , 2012, PloS one.

[130]  K. Parker,et al.  Multiplexed Protein Quantitation in Saccharomyces cerevisiae Using Amine-reactive Isobaric Tagging Reagents*S , 2004, Molecular & Cellular Proteomics.