A miRNA-regulatory network explains how dysregulated miRNAs perturb oncogenic processes across diverse cancers

Genes regulated by the same miRNA can be discovered by virtue of their coexpression at the transcriptional level and the presence of a conserved miRNA-binding site in their 3' UTRs. Using this principle we have integrated the three best performing and complementary algorithms into a framework for inference of regulation by miRNAs (FIRM) from sets of coexpressed genes. We demonstrate the utility of FIRM by inferring a cancer-miRNA regulatory network through the analysis of 2240 gene coexpression signatures from 46 cancers. By analyzing this network for functional enrichment of known hallmarks of cancer we have discovered a subset of 13 miRNAs that regulate oncogenic processes across diverse cancers. We have performed experiments to test predictions from this miRNA-regulatory network to demonstrate that miRNAs of the miR-29 family (miR-29a, miR-29b, and miR-29c) regulate specific genes associated with tissue invasion and metastasis in lung adenocarcinoma. Further, we highlight the specificity of using FIRM inferences to identify miRNA-regulated genes by experimentally validating that miR-767-5p, which partially shares the miR-29 seed sequence, regulates only a subset of miR-29 targets. By providing mechanistic linkage between miRNA dysregulation in cancer, their binding sites in the 3'UTRs of specific sets of coexpressed genes, and their associations with known hallmarks of cancer, FIRM, and the inferred cancer miRNA-regulatory network will serve as a powerful public resource for discovery of potential cancer biomarkers.

[1]  Albert,et al.  Emergence of scaling in random networks , 1999, Science.

[2]  D. Hanahan,et al.  The Hallmarks of Cancer , 2000, Cell.

[3]  D. Lockhart,et al.  Analysis of gene expression profiles in normal and neoplastic ovarian tissue samples identifies candidate molecular markers of epithelial ovarian cancer. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[4]  E. Lander,et al.  Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[5]  David E. Misek,et al.  Gene-expression profiles predict survival of patients with lung adenocarcinoma , 2002, Nature Medicine.

[6]  C. Perou,et al.  Molecular classification of head and neck squamous cell carcinomas using patterns of gene expression , 2004 .

[7]  Thomas Lengauer,et al.  ROCR: visualizing classifier performance in R , 2005, Bioinform..

[8]  Robert B. Russell,et al.  Principles of MicroRNATarget Recognition , 2005 .

[9]  R. Russell,et al.  Principles of MicroRNA–Target Recognition , 2005, PLoS biology.

[10]  J. Castle,et al.  Microarray analysis shows that some microRNAs downregulate large numbers of target mRNAs , 2005, Nature.

[11]  Graziano Pesole,et al.  MoD Tools: regulatory motif discovery in nucleotide sequences from co-regulated or homologous genes , 2006, Nucleic Acids Res..

[12]  T. Dalmay,et al.  MicroRNAs and the hallmarks of cancer , 2006, Oncogene.

[13]  David J. Reiss,et al.  Integrated biclustering of heterogeneous genome-wide datasets for the inference of global regulatory networks , 2006, BMC Bioinformatics.

[14]  R. Stephens,et al.  Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. , 2006, Cancer cell.

[15]  C. Eng,et al.  A limited set of human MicroRNA is deregulated in follicular thyroid carcinoma. , 2006, The Journal of clinical endocrinology and metabolism.

[16]  A. Hatzigeorgiou,et al.  A guide through present computational approaches for the identification of mammalian microRNA targets , 2006, Nature Methods.

[17]  Holger Fröhlich,et al.  GOSim – an R-package for computation of information theoretic GO similarities between terms and gene products , 2007, BMC Bioinformatics.

[18]  Thomas Lengauer,et al.  Improved scoring of functional groups from gene expression data by decorrelating GO graph structure , 2006, Bioinform..

[19]  Xiaowei Wang,et al.  Systematic identification of microRNA functions by combining target prediction and expression profiling , 2006, Nucleic acids research.

[20]  H. Sültmann,et al.  The human let-7a-3 locus contains an epigenetically regulated microRNA gene with oncogenic function. , 2007, Cancer research.

[21]  F. Slack,et al.  The let-7 microRNA represses cell proliferation pathways in human cells. , 2007, Cancer research.

[22]  Detection of a MicroRNA Signal in an In Vivo Expression Set of mRNAs , 2007, PloS one.

[23]  Zhenyu Xuan,et al.  A biochemical approach to identifying microRNA targets , 2007, Proceedings of the National Academy of Sciences.

[24]  L. Lim,et al.  Transcripts Targeted by the MicroRNA-16 Family Cooperatively Regulate Cell Cycle Progression , 2007, Molecular and Cellular Biology.

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

[26]  L. Lim,et al.  A microRNA component of the p53 tumour suppressor network , 2007, Nature.

[27]  Michael A. Beer,et al.  Transactivation of miR-34a by p53 broadly influences gene expression and promotes apoptosis. , 2007, Molecular cell.

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

[29]  Daniel Herschlag,et al.  Systematic Identification of mRNAs Recruited to Argonaute 2 by Specific microRNAs and Corresponding Changes in Transcript Abundance , 2008, PloS one.

[30]  A. Krogh,et al.  Programmed Cell Death 4 (PDCD4) Is an Important Functional Target of the MicroRNA miR-21 in Breast Cancer Cells* , 2008, Journal of Biological Chemistry.

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

[32]  R. Shamir,et al.  Transcription factor and microRNA motif discovery: the Amadeus platform and a compendium of metazoan target sets. , 2008, Genome research.

[33]  C. Creighton,et al.  Widespread deregulation of microRNA expression in human prostate cancer , 2008, Oncogene.

[34]  Aimee L Jackson,et al.  Coordinated regulation of cell cycle transcripts by p53-Inducible microRNAs, miR-192 and miR-215. , 2008, Cancer research.

[35]  N. Rajewsky,et al.  Widespread changes in protein synthesis induced by microRNAs , 2008, Nature.

[36]  D. Bartel,et al.  The impact of microRNAs on protein output , 2008, Nature.

[37]  Paul Ahlquist,et al.  MicroRNA 29c is down-regulated in nasopharyngeal carcinomas, up-regulating mRNAs encoding extracellular matrix proteins , 2008, Proceedings of the National Academy of Sciences.

[38]  William Ritchie,et al.  Conserved Expression Patterns Predict microRNA Targets , 2009, PLoS Comput. Biol..

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

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

[41]  Manuel A. S. Santos,et al.  MicroRNA-155 modulates the interleukin-1 signaling pathway in activated human monocyte-derived dendritic cells , 2009, Proceedings of the National Academy of Sciences.

[42]  M. Henry,et al.  MiRNA-29a regulates the expression of numerous proteins and reduces the invasiveness and proliferation of human carcinoma cell lines. , 2009, European journal of cancer.

[43]  O. Larsson,et al.  Comparison and Integration of Current Computational Methods Regulatory Element Identification in Subsets of Transcripts: Material Supplemental Regulatory Element Identification in Subsets of Transcripts: Comparison and Integration of Current Computational Methods , 2022 .

[44]  Hugues Sicotte,et al.  Genome-Wide Transcriptional Profiling Reveals MicroRNA-Correlated Genes and Biological Processes in Human Lymphoblastoid Cell Lines , 2009, PloS one.

[45]  Gerben Duns,et al.  A high throughput experimental approach to identify miRNA targets in human cells , 2009, Nucleic acids research.

[46]  G. Calin,et al.  An Integrated Approach for Experimental Target Identification of Hypoxia-induced miR-210* , 2009, The Journal of Biological Chemistry.

[47]  Christoph Rodak,et al.  MirZ: an integrated microRNA expression atlas and target prediction resource , 2009, Nucleic Acids Res..

[48]  Yadong Wang,et al.  miR2Disease: a manually curated database for microRNA deregulation in human disease , 2008, Nucleic Acids Res..

[49]  Xiaoguang Fang,et al.  MicroRNAs: novel regulators in the hallmarks of human cancer. , 2009, Cancer letters.

[50]  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 .

[51]  Hsien-Da Huang,et al.  MicroRNA‐122, a tumor suppressor microRNA that regulates intrahepatic metastasis of hepatocellular carcinoma , 2009, Hepatology.

[52]  O. Elemento,et al.  Revealing global regulatory perturbations across human cancers. , 2009, Molecular cell.

[53]  Xavier Robin,et al.  pROC: an open-source package for R and S+ to analyze and compare ROC curves , 2011, BMC Bioinformatics.

[54]  Kai Stühler,et al.  Identification and Functional Characterization of microRNAs Involved in the Malignant Progression of Gliomas , 2010, Brain pathology.

[55]  Yingdong Zhao,et al.  MicroRNA Expression Differentiates Histology and Predicts Survival of Lung Cancer , 2010, Clinical Cancer Research.

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

[57]  Peter T Nelson,et al.  Anti-Argonaute RIP-Chip shows that miRNA transfections alter global patterns of mRNA recruitment to microribonucleoprotein complexes. , 2010, RNA.

[58]  Nitin S. Baliga,et al.  miRvestigator: web application to identify miRNAs responsible for co-regulated gene expression patterns discovered through transcriptome profiling , 2011, Nucleic Acids Res..

[59]  C. Croce,et al.  MicroRNAs as therapeutic targets in cancer. , 2011, Translational research : the journal of laboratory and clinical medicine.

[60]  J. Qian,et al.  miR-29 is a major regulator of genes associated with pulmonary fibrosis. , 2011, American journal of respiratory cell and molecular biology.

[61]  Oliver Hofmann,et al.  Capture of MicroRNA–Bound mRNAs Identifies the Tumor Suppressor miR-34a as a Regulator of Growth Factor Signaling , 2011, PLoS genetics.

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

[63]  Ana Kozomara,et al.  miRBase: integrating microRNA annotation and deep-sequencing data , 2010, Nucleic Acids Res..

[64]  C. Croce,et al.  microRNAs: Master regulators as potential therapeutics in cancer. , 2011, Annual review of pharmacology and toxicology.

[65]  K. Zen,et al.  Circulating MicroRNAs: a novel class of biomarkers to diagnose and monitor human cancers , 2012, Medicinal research reviews.

[66]  M. Tschan,et al.  MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma , 2012, Oncogene.

[67]  C. Augello,et al.  miR-296 regulation of a cell polarity-cell plasticity module controls tumor progression , 2011, Oncogene.

[68]  J. Hackermüller,et al.  MiR-130a, miR-203 and miR-205 jointly repress key oncogenic pathways and are downregulated in prostate carcinoma , 2013, Oncogene.