Competing endogenous RNA networks: tying the essential knots for cancer biology and therapeutics

A recently discovered dimension of post-transcriptional gene regulation involves co-regulatory crosstalk between RNA transcripts, which compete for common pools of microRNA (miRNA) molecules. These competing endogenous RNAs (ceRNAs), or natural miRNA sponges, have an active role in regulating miRNA availability within the cell and form intertwined regulatory networks. Recent reports have implicated diverse RNA species including protein-coding messenger RNAs and non-coding RNAs as ceRNAs in human development and diseases including human cancer. In this review, we discuss the most recent discoveries that implicate natural miRNA decoys in human cancer biology, as well as exciting advances in the study of ceRNA networks and dynamics. The structure and topology of intricate genome-scale ceRNA networks can be predicted computationally, and their dynamic response to fluctuations in ceRNA and miRNA levels can be studied via mathematical modeling. Additionally, the development of new methods to quantitatively determine absolute expression levels of miRNA and ceRNA molecules have expanded the capacity to accurately study the efficiency of ceRNA crosstalk in diverse biological models. These major milestones are of critical importance to identify key components of ceRNA regulatory networks that could aid the development of new approaches to cancer diagnostics and oligonucleotide-based therapeutics.

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

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

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

[4]  C. Sander,et al.  Genome-wide analysis of non-coding regulatory mutations in cancer , 2014, Nature Genetics.

[5]  Q. Cui,et al.  An Analysis of Human MicroRNA and Disease Associations , 2008, PloS one.

[6]  C. Bracken,et al.  Experimental strategies for microRNA target identification , 2011, Nucleic acids research.

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

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

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

[10]  Riccardo Zecchina,et al.  Modelling Competing Endogenous RNA Networks , 2013, PloS one.

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

[12]  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.

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

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

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

[16]  R. Agami,et al.  MicroRNA regulation by RNA-binding proteins and its implications for cancer , 2011, Nature Reviews Cancer.

[17]  D. Tollervey.  Molecular biology: RNA lost in translation , 2006, Nature.

[18]  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.

[19]  Juan Liu,et al.  Construction and investigation of breast-cancer-specific ceRNA network based on the mRNA and miRNA expression data. , 2014, IET systems biology.

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

[21]  Burton B. Yang,et al.  The non-coding 3′ UTR of CD44 induces metastasis by regulating extracellular matrix functions , 2012, Journal of Cell Science.

[22]  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.

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

[24]  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.

[25]  D. Boomsma,et al.  Regular Exercise, Subjective Wellbeing, and Internalizing Problems in Adolescence: Causality or Genetic Pleiotropy? , 2012, Front. Gene..

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

[27]  M. Manikandan,et al.  Single nucleotide polymorphisms in microRNA binding sites of oncogenes: implications in cancer and pharmacogenomics. , 2014, Omics : a journal of integrative biology.

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

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

[30]  George A Calin,et al.  MicroRNAs and ceRNAs: therapeutic implications of RNA networks , 2014, Expert opinion on biological therapy.

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

[32]  Hanah Margalit,et al.  Interactions between Distant ceRNAs in Regulatory Networks , 2014, Biophysical journal.

[33]  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.

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

[35]  Yanchun Liang,et al.  3′UTR shortening identifies high-risk cancers with targeted dysregulation of the ceRNA network , 2014, Scientific Reports.

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

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

[38]  X. Ye,et al.  Hepatitis B Virus mRNA-Mediated miR-122 Inhibition Upregulates PTTG1-Binding Protein, Which Promotes Hepatocellular Carcinoma Tumor Growth and Cell Invasion , 2012, Journal of Virology.

[39]  Nicolas E. Buchler,et al.  Molecular titration and ultrasensitivity in regulatory networks. , 2008, Journal of molecular biology.

[40]  A. Bader.  miR-34 – a microRNA replacement therapy is headed to the clinic , 2012, Front. Gene..

[41]  Matteo Figliuzzi,et al.  RNA-based regulation: dynamics and response to perturbations of competing RNAs. , 2013, Biophysical journal.

[42]  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..

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

[44]  Matteo Figliuzzi,et al.  MicroRNAs as a selective channel of communication between competing RNAs: a steady-state theory. , 2012, Biophysical journal.

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

[46]  R. Sachidanandam,et al.  High-throughput assessment of microRNA activity and function using microRNA sensor and decoy libraries , 2012, Nature Methods.

[47]  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.

[48]  C. Croce,et al.  Frequent deletions and down-regulation of micro- RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[51]  Lorenzo Farina,et al.  Computational analysis identifies a sponge interaction network between long non-coding RNAs and messenger RNAs in human breast cancer , 2014, BMC Systems Biology.

[52]  C. Fabián Flores-Jasso,et al.  Argonaute Divides Its RNA Guide into Domains with Distinct Functions and RNA-Binding Properties , 2012, Cell.

[53]  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.

[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]  P. Harrison,et al.  Mining Mammalian Transcript Data for Functional Long Non-Coding RNAs , 2010, PloS one.

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

[57]  Mingming Jia,et al.  COSMIC: exploring the world's knowledge of somatic mutations in human cancer , 2014, Nucleic Acids Res..

[58]  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.

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

[60]  Christopher J. Cheng,et al.  MicroRNA silencing for cancer therapy targeted to the tumor microenvironment , 2014, Nature.

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

[62]  J. Lieberman,et al.  Desperately seeking microRNA targets , 2010, Nature Structural &Molecular Biology.

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

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

[65]  Burton B. Yang,et al.  The non-coding 3′ UTR of CD44 induces metastasis by regulating extracellular matrix functions , 2012, Journal of Cell Science.

[66]  Yen-Jen Oyang,et al.  MicroRNA-mediated networks underlie immune response regulation in papillary thyroid carcinoma , 2014, Scientific Reports.

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

[68]  Min Pan,et al.  A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers , 2012, Genome research.

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

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

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

[72]  C. Croce,et al.  MicroRNA signatures in human cancers , 2006, Nature Reviews Cancer.

[73]  Andreas Heger,et al.  Evidence for conserved post-transcriptional roles of unitary pseudogenes and for frequent bifunctionality of mRNAs , 2012, Genome Biology.

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

[75]  Xiaodong Song,et al.  Analysing the relationship between lncRNA and protein-coding gene and the role of lncRNA as ceRNA in pulmonary fibrosis , 2014, Journal of cellular and molecular medicine.

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

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