Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma

Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.

[1]  Zhongming Zhao,et al.  A comparative study of cancer proteins in the human protein-protein interaction network , 2010, BMC Genomics.

[2]  Xi Chen,et al.  An efficient hierarchical generalized linear mixed model for pathway analysis of genome-wide association studies , 2011, Bioinform..

[3]  An-Yuan Guo,et al.  A Novel microRNA and transcription factor mediated regulatory network in schizophrenia , 2010, BMC Systems Biology.

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

[5]  Hiroyuki Ogata,et al.  KEGG: Kyoto Encyclopedia of Genes and Genomes , 1999, Nucleic Acids Res..

[6]  E. Holland,et al.  Glioblastoma multiforme: the terminator. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[7]  Alexander E. Kel,et al.  TRANSFAC® and its module TRANSCompel®: transcriptional gene regulation in eukaryotes , 2005, Nucleic Acids Res..

[8]  Jana Novakova,et al.  MicroRNA involvement in glioblastoma pathogenesis. , 2009, Biochemical and biophysical research communications.

[9]  Jennifer A Fulcher,et al.  Phagocytes, Granulocytes, and Myelopoiesis , 2022 .

[10]  Lynn Doucette-Stamm,et al.  A C . elegans genome-scale microRNA network contains composite feedback motifs with high flux capacity , 2008 .

[11]  Y. Benjamini,et al.  Controlling the false discovery rate: a practical and powerful approach to multiple testing , 1995 .

[12]  Mitchel S Berger,et al.  Contribution of Notch signaling activation to human glioblastoma multiforme. , 2007, Journal of neurosurgery.

[13]  Torbjörn E. M. Nordling,et al.  Network modeling of the transcriptional effects of copy number aberrations in glioblastoma , 2011, Molecular systems biology.

[14]  S. Gabriel,et al.  Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2010, Cancer cell.

[15]  Francesco Tomasello,et al.  miR-21 and 221 upregulation and miR-181b downregulation in human grade II–IV astrocytic tumors , 2009, Journal of Neuro-Oncology.

[16]  Alexander E. Kel,et al.  MATCHTM: a tool for searching transcription factor binding sites in DNA sequences , 2003, Nucleic Acids Res..

[17]  Anton J. Enright,et al.  Detection of functional modules from protein interaction networks , 2003, Proteins.

[18]  Adam A. Margolin,et al.  Reverse engineering cellular networks , 2006, Nature Protocols.

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

[20]  Alexander R. Pico,et al.  Variants in the CDKN2B and RTEL1 regions are associated with high grade glioma susceptibility , 2009, Nature Genetics.

[21]  Yunqing Li,et al.  MicroRNA-34a inhibits glioblastoma growth by targeting multiple oncogenes. , 2009, Cancer research.

[22]  Dianne P. O'Leary,et al.  Why Do Hubs in the Yeast Protein Interaction Network Tend To Be Essential: Reexamining the Connection between the Network Topology and Essentiality , 2008, PLoS Comput. Biol..

[23]  C. Burge,et al.  Prediction of Mammalian MicroRNA Targets , 2003, Cell.

[24]  Sharmila Shankar,et al.  Targeting Epigenetic Regulation of miR-34a for Treatment of Pancreatic Cancer by Inhibition of Pancreatic Cancer Stem Cells , 2011, PloS one.

[25]  L. Holm,et al.  The Pfam protein families database , 2005, Nucleic Acids Res..

[26]  E. Davidson.  The Regulatory Genome: Gene Regulatory Networks In Development And Evolution , 2006 .

[27]  A. van Oudenaarden,et al.  MicroRNA-mediated feedback and feedforward loops are recurrent network motifs in mammals. , 2007, Molecular cell.

[28]  O. Hobert.  Gene Regulation by Transcription Factors and MicroRNAs , 2008, Science.

[29]  Yun Xiao,et al.  MiRNA–miRNA synergistic network: construction via co-regulating functional modules and disease miRNA topological features , 2010, Nucleic acids research.

[30]  Chris Wiggins,et al.  ARACNE: An Algorithm for the Reconstruction of Gene Regulatory Networks in a Mammalian Cellular Context , 2004, BMC Bioinformatics.

[31]  Benjamin Purow,et al.  Advances in the genetics of glioblastoma: are we reaching critical mass? , 2009, Nature Reviews Neurology.

[32]  Qing-Rong Chen,et al.  Systematic proteome analysis identifies transcription factor YY1 as a direct target of miR-34a. , 2011, Journal of proteome research.

[33]  Claudia Petritsch,et al.  miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells , 2008 .

[34]  Yuri Kotliarov,et al.  Prediction of Associations between microRNAs and Gene Expression in Glioma Biology , 2011, PloS one.

[35]  Melissa Bondy,et al.  Genome-wide association study identifies five susceptibility loci for glioma , 2009, Nature Genetics.

[36]  Yong Jin Choi,et al.  miR-34 miRNAs provide a barrier for somatic cell reprogramming , 2011, Nature Cell Biology.

[37]  Kai-Fai Lee,et al.  MicroRNA-34a suppresses invasion through downregulation of Notch1 and Jagged1 in cervical carcinoma and choriocarcinoma cells. , 2010, Carcinogenesis.

[38]  Trey Ideker,et al.  Cytoscape 2.8: new features for data integration and network visualization , 2010, Bioinform..

[39]  S. Ivy,et al.  Targeting cancer stem cells by inhibiting Wnt, Notch, and Hedgehog pathways , 2011, Nature Reviews Clinical Oncology.

[40]  Sharon J. Diskin,et al.  A Functional Screen Identifies miR-34a as a Candidate Neuroblastoma Tumor Suppressor Gene , 2008, Molecular Cancer Research.

[41]  E. Birney,et al.  Pfam: the protein families database , 2013, Nucleic Acids Res..

[42]  Joshua M. Korn,et al.  Comprehensive genomic characterization defines human glioblastoma genes and core pathways , 2008, Nature.

[43]  C. Croce,et al.  A microRNA expression signature of human solid tumors defines cancer gene targets , 2006, Proceedings of the National Academy of Sciences of the United States of America.

[44]  Fei Chen,et al.  Effect of microRNA‐34a in cell cycle, differentiation, and apoptosis: A review , 2012, Journal of biochemical and molecular toxicology.

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

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

[47]  Sujaya Srinivasan,et al.  A Ten-microRNA Expression Signature Predicts Survival in Glioblastoma , 2011, PloS one.

[48]  Tom H. Pringle,et al.  The human genome browser at UCSC. , 2002, Genome research.

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

[50]  Alice Shapiro,et al.  MicroRNA-21 targets a network of key tumor-suppressive pathways in glioblastoma cells. , 2008, Cancer research.

[51]  T. Wurdinger,et al.  MicroRNA 21 Promotes Glioma Invasion by Targeting Matrix Metalloproteinase Regulators , 2008, Molecular and Cellular Biology.

[52]  W. Cho.  OncomiRs: the discovery and progress of microRNAs in cancers , 2007, Molecular Cancer.

[53]  Yibo Wu,et al.  GOSemSim: an R package for measuring semantic similarity among GO terms and gene products , 2010, Bioinform..

[54]  Alan F. Scott,et al.  McKusick's Online Mendelian Inheritance in Man (OMIM®) , 2008, Nucleic Acids Res..

[55]  C. Sander,et al.  Automated Network Analysis Identifies Core Pathways in Glioblastoma , 2010, PloS one.

[56]  Dustin E. Schones,et al.  Chromatin poises miRNA- and protein-coding genes for expression. , 2009, Genome research.

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

[58]  Yitzhak Pilpel,et al.  Global and Local Architecture of the Mammalian microRNA–Transcription Factor Regulatory Network , 2007, PLoS Comput. Biol..

[59]  E. Wingender,et al.  MATCH: A tool for searching transcription factor binding sites in DNA sequences. , 2003, Nucleic acids research.

[60]  J Khan,et al.  The MYCN oncogene is a direct target of miR-34a , 2008, Oncogene.

[61]  Yanghua Xiao,et al.  Integrated analysis of mutations, miRNA and mRNA expression in glioblastoma , 2010, BMC Systems Biology.

[62]  D. Goldberg,et al.  Assessing experimentally derived interactions in a small world , 2003, Proceedings of the National Academy of Sciences of the United States of America.

[63]  N. Campbell.  Genetic association database , 2004, Nature Reviews Genetics.

[64]  S. L. Wong,et al.  Motifs, themes and thematic maps of an integrated Saccharomyces cerevisiae interaction network , 2005, Journal of biology.

[65]  Mingming Jia,et al.  COSMIC: mining complete cancer genomes in the Catalogue of Somatic Mutations in Cancer , 2010, Nucleic Acids Res..

[66]  Giuseppe Basso,et al.  MiR-34a Targeting of Notch Ligand Delta-Like 1 Impairs CD15+/CD133+ Tumor-Propagating Cells and Supports Neural Differentiation in Medulloblastoma , 2011, PloS one.

[67]  Shipra Agrawal,et al.  Cancer esearch rated Systems and Technologies blastoma-Specific Protein Interaction Network Identifies A and CSK 21 as Connecting Molecules between R l Cycle – Associated Genes , 2010 .

[68]  M. Gerstein,et al.  Genomic analysis of essentiality within protein networks. , 2004, Trends in genetics : TIG.

[69]  S. Shen-Orr,et al.  Network motifs in the transcriptional regulation network of Escherichia coli , 2002, Nature Genetics.

[70]  Bing Zhang,et al.  WebGestalt: an integrated system for exploring gene sets in various biological contexts , 2005, Nucleic Acids Res..

[71]  Yunqing Li,et al.  microRNA-34a is tumor suppressive in brain tumors and glioma stem cells , 2010, Cell cycle.

[72]  Q. Su,et al.  Expression of Notch-1 and its ligands, Delta-like-1 and Jagged-1, is critical for glioma cell survival and proliferation. , 2005, Cancer research.

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

[74]  B. Sosa-Pineda,et al.  The gene Pax4 is an essential regulator of pancreatic beta-cell development. , 2004, Molecules and cells.

[75]  Tae-Min Kim,et al.  A developmental taxonomy of glioblastoma defined and maintained by MicroRNAs. , 2011, Cancer research.

[76]  F. Ferrari,et al.  Motif discovery in promoters of genes co-localized and co-expressed during myeloid cells differentiation , 2008, Nucleic acids research.

[77]  K. Kosik,et al.  MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. , 2005, Cancer research.

[78]  Gabriele Schackert,et al.  Long-term survival with glioblastoma multiforme. , 2007, Brain : a journal of neurology.

[79]  Robert W. Zeller,et al.  miR-124 function during Ciona intestinalis neuronal development includes extensive interaction with the Notch signaling pathway , 2011, Development.

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

[81]  J. Parker,et al.  A feed-forward loop involving protein kinase Calpha and microRNAs regulates tumor cell cycle. , 2009, Cancer research.

[82]  A. Barabasi,et al.  Network biology: understanding the cell's functional organization , 2004, Nature Reviews Genetics.

[83]  D. Busam,et al.  An Integrated Genomic Analysis of Human Glioblastoma Multiforme , 2008, Science.

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

[85]  Varda Rotter,et al.  Coupling transcriptional and post-transcriptional miRNA regulation in the control of cell fate , 2009, Aging.

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

[87]  Illés J. Farkas,et al.  CFinder: locating cliques and overlapping modules in biological networks , 2006, Bioinform..

[88]  Fabian J Theis,et al.  PhenomiR: a knowledgebase for microRNA expression in diseases and biological processes , 2010, Genome Biology.

[89]  Bing Zhang,et al.  Network-assisted protein identification and data interpretation in shotgun proteomics , 2009, Molecular systems biology.

[90]  Benjamin Purow,et al.  The elephant in the room: do microRNA-based therapies have a realistic chance of succeeding for brain tumors such as glioblastoma? , 2011, Journal of Neuro-Oncology.