miRNA‐mediated ‘tug‐of‐war’ model reveals ceRNA propensity of genes in cancers

Competing endogenous RNA (ceRNA) are transcripts that cross‐regulate each other at the post‐transcriptional level by competing for shared microRNA response elements (MREs). These have been implicated in various biological processes impacting cell‐fate decisions and diseases including cancer. There are several studies that predict possible ceRNA pairs by adopting various machine‐learning and mathematical approaches; however, there is no method that enables us to gauge as well as compare the propensity of the ceRNA of a gene and precisely envisages which among a pair exerts a stronger pull on the shared miRNA pool. In this study, we developed a method that uses the ‘tug of war of genes’ concept to predict and quantify ceRNA potential of a gene for the shared miRNA pool in cancers based on a score represented by SoCeR (score of competing endogenous RNA). The method was executed on the RNA‐Seq transcriptional profiles of genes and miRNA available at TCGA along with CLIP‐supported miRNA‐target sites to predict ceRNA in 32 cancer types which were validated with already reported cases. The proposed method can be used to determine the sequestering capability of the gene of interest as well as in ranking the probable ceRNA candidates of a gene. Finally, we developed standalone applications (SoCeR tool) to aid researchers in easier implementation of the method in analysing different data sets or diseases.

[1]  Yufei Huang,et al.  TraceRNA: A Web Application for Competing Endogenous RNA Exploration , 2014, Circulation. Cardiovascular genetics.

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

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

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

[6]  Doron Betel,et al.  The microRNA.org resource: targets and expression , 2007, Nucleic Acids Res..

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

[8]  William A. Rennie,et al.  STarMirDB: A database of microRNA binding sites , 2016, RNA biology.

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

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

[11]  Guangya Wang,et al.  IGF1 3′UTR functions as a ceRNA in promoting angiogenesis by sponging miR-29 family in osteosarcoma , 2016, Journal of Molecular Histology.

[12]  Subbaya Subramanian,et al.  Competing endogenous RNA database , 2012, Bioinformation.

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

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

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

[16]  Pier Paolo Pandolfi,et al.  Subtle variations in Pten dose determine cancer susceptibility , 2010, Nature Genetics.

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

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

[19]  Vikram Agarwal,et al.  Impact of MicroRNA Levels, Target-Site Complementarity, and Cooperativity on Competing Endogenous RNA-Regulated Gene Expression , 2016, Molecular cell.

[20]  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.

[21]  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.

[22]  Anton J. Enright,et al.  spongeScan: A web for detecting microRNA binding elements in lncRNA sequences , 2016, Nucleic Acids Res..

[23]  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.

[24]  Tao Xi,et al.  CXCR4 3'UTR functions as a ceRNA in promoting metastasis, proliferation and survival of MCF-7 cells by regulating miR-146a activity. , 2015, European journal of cell biology.

[25]  Tingting Shao,et al.  The mRNA related ceRNA–ceRNA landscape and significance across 20 major cancer types , 2015, Nucleic acids research.

[26]  M. Kloc.  Emerging novel functions of RNAs, and binary phenotype? , 2008, Developmental biology.

[27]  P. Pandolfi,et al.  Pten Dose Dictates Cancer Progression in the Prostate , 2003, PLoS biology.

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

[29]  S. Li,et al.  Expression and role of oncogenic miRNA-224 in esophageal squamous cell carcinoma , 2015, BMC Cancer.

[30]  Devyani Samantarrai,et al.  miR‐429 inhibits metastasis by targeting KIAA0101 in Soft Tissue Sarcoma , 2017, Experimental cell research.

[31]  Ana Kozomara,et al.  miRBase: annotating high confidence microRNAs using deep sequencing data , 2013, Nucleic Acids Res..

[32]  Abygail M. Gumbayan,et al.  Properties and kinetics of microRNA regulation through canonical seed sites , 2015, Journal of RNAi and gene silencing : an international journal of RNA and gene targeting research.

[33]  Anjali J. Koppal,et al.  Supplementary data: Comprehensive modeling of microRNA targets predicts functional non-conserved and non-canonical sites , 2010 .

[34]  D. Bartel,et al.  Predicting effective microRNA target sites in mammalian mRNAs , 2015, eLife.

[35]  Ling Fang,et al.  Expression of CD44 3′-untranslated region regulates endogenous microRNA functions in tumorigenesis and angiogenesis , 2010, Nucleic acids research.

[36]  L. Lim,et al.  MicroRNA targeting specificity in mammals: determinants beyond seed pairing. , 2007, Molecular cell.

[37]  Hong Zhu,et al.  MiR-130b plays an oncogenic role by repressing PTEN expression in esophageal squamous cell carcinoma cells , 2015, BMC Cancer.

[38]  Tao Xi,et al.  STARD13-correlated ceRNA network inhibits EMT and metastasis of breast cancer , 2016, Oncotarget.

[39]  P. Goodfellow,et al.  Phosphatase and tensin homolog (PTEN) pseudogene expression in endometrial cancer: a conserved regulatory mechanism important in tumorigenesis? , 2011, Gynecologic oncology.

[40]  William A. Rennie,et al.  CLIP-based prediction of mammalian microRNA binding sites , 2013, Nucleic acids research.

[41]  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..

[42]  Salvatore Alaimo,et al.  A novel computational method for inferring competing endogenous interactions , 2016, Briefings Bioinform..

[43]  R. Gatenby,et al.  Models of tumor-host interaction as competing populations: implications for tumor biology and treatment. , 1995, Journal of theoretical biology.

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

[45]  Zhen Chen,et al.  ROR functions as a ceRNA to regulate Nanog expression by sponging miR-145 and predicts poor prognosis in pancreatic cancer , 2015, Oncotarget.

[46]  Chengping Hu,et al.  Competing endogenous RNA in cancer: a new pattern of gene expression regulation. , 2015, International journal of clinical and experimental medicine.

[47]  Bibekanand Mallick,et al.  Altered gene expression in late-onset Alzheimer's disease due to SNPs within 3'UTR microRNA response elements. , 2017, Genomics.

[48]  M. Mukaka,et al.  Statistics corner: A guide to appropriate use of correlation coefficient in medical research. , 2012, Malawi medical journal : the journal of Medical Association of Malawi.

[49]  W. Cavenee,et al.  A mutant epidermal growth factor receptor common in human glioma confers enhanced tumorigenicity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

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

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

[52]  Shaoli Das,et al.  lnCeDB: Database of Human Long Noncoding RNA Acting as Competing Endogenous RNA , 2014, PloS one.

[53]  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.

[54]  Burton B. Yang,et al.  A 3′-Untranslated Region (3′UTR) Induces Organ Adhesion by Regulating miR-199a* Functions , 2009, PloS one.

[55]  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.

[56]  Lin Zhao,et al.  LincRNA-ROR induces epithelial-to-mesenchymal transition and contributes to breast cancer tumorigenesis and metastasis , 2014, Cell Death and Disease.