Identifying the miRNA Signature Association with Aging-Related Senescence in Glioblastoma

Glioblastoma (GBM) is the most common malignant brain tumor and its malignant phenotypic characteristics are classified as grade IV tumors. Molecular interactions, such as protein–protein, protein–ncRNA, and protein–peptide interactions are crucial to transfer the signaling communications in cellular signaling pathways. Evidences suggest that signaling pathways of stem cells are also activated, which helps the propagation of GBM. Hence, it is important to identify a common signaling pathway that could be visible from multiple GBM gene expression data. microRNA signaling is considered important in GBM signaling, which needs further validation. We performed a high-throughput analysis using micro array expression profiles from 574 samples to explore the role of non-coding RNAs in the disease progression and unique signaling communication in GBM. A series of computational methods involving miRNA expression, gene ontology (GO) based gene enrichment, pathway mapping, and annotation from metabolic pathways databases, and network analysis were used for the analysis. Our study revealed the physiological roles of many known and novel miRNAs in cancer signaling, especially concerning signaling in cancer progression and proliferation. Overall, the results revealed a strong connection with stress induced senescence, significant miRNA targets for cell cycle arrest, and many common signaling pathways to GBM in the network.

[1]  J. Roliński,et al.  TLR-4 Signaling vs. Immune Checkpoints, miRNAs Molecules, Cancer Stem Cells, and Wingless-Signaling Interplay in Glioblastoma Multiforme—Future Perspectives , 2020, International journal of molecular sciences.

[2]  P. Ruusuvuori,et al.  Glioblastoma Multiforme Stem Cell Cycle Arrest by Alkylaminophenol through the Modulation of EGFR and CSC Signaling Pathways , 2020, Cells.

[3]  J. Roliński,et al.  Micro RNA Molecules as Modulators of Treatment Resistance, Immune Checkpoints Controllers and Sensitive Biomarkers in Glioblastoma Multiforme , 2020, International journal of molecular sciences.

[4]  O. Yli-Harja,et al.  Alkylaminophenol Induces G1/S Phase Cell Cycle Arrest in Glioblastoma Cells Through p53 and Cyclin-Dependent Kinase Signaling Pathway , 2019, Front. Pharmacol..

[5]  Yang Jiang,et al.  Bioinformatic analyses reveal a distinct Notch activation induced by STAT3 phosphorylation in the mesenchymal subtype of glioblastoma. , 2017, Journal of neurosurgery.

[6]  M. Davis Glioblastoma: Overview of Disease and Treatment. , 2016, Clinical journal of oncology nursing.

[7]  Yu-guang Liu,et al.  Aging-related gene signature regulated by Nlrp3 predicts glioma progression. , 2015, American journal of cancer research.

[8]  Lun Dong,et al.  miRNA microarray reveals specific expression in the peripheral blood of glioblastoma patients. , 2014, International journal of oncology.

[9]  M. Gilbert Faculty Opinions recommendation of Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. , 2014 .

[10]  M. Borowiec,et al.  The Failure in the Stabilization of Glioblastoma-Derived Cell Lines: Spontaneous In Vitro Senescence as the Main Culprit , 2014, PloS one.

[11]  Margaret C. Cam,et al.  Age-Specific Signatures of Glioblastoma at the Genomic, Genetic, and Epigenetic Levels , 2013, BCB.

[12]  J. Campisi Aging, cellular senescence, and cancer. , 2013, Annual review of physiology.

[13]  H. H. Andersen,et al.  A Systematic Review of MicroRNA in Glioblastoma Multiforme: Micro-modulators in the Mesenchymal Mode of Migration and Invasion , 2012, Molecular Neurobiology.

[14]  Mario Cannataro,et al.  Semantic similarity analysis of protein data: assessment with biological features and issues , 2012, Briefings Bioinform..

[15]  J. Tonn,et al.  MiRNA expression patterns predict survival in glioblastoma , 2011, Radiation oncology.

[16]  P. Birner,et al.  Expression of mutated isocitrate dehydrogenase-1 in gliomas is associated with p53 and EGFR expression. , 2011, Folia neuropathologica.

[17]  R. Scarpulla,et al.  Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. , 2011, Biochimica et biophysica acta.

[18]  Peer Bork,et al.  Interactive Tree Of Life v2: online annotation and display of phylogenetic trees made easy , 2011, Nucleic Acids Res..

[19]  S. Rodriguez-Zas,et al.  Cell cycle and aging, morphogenesis, and response to stimuli genes are individualized biomarkers of glioblastoma progression and survival , 2011, BMC Medical Genomics.

[20]  P. López-Romero Pre-processing and differential expression analysis of Agilent microRNA arrays using the AgiMicroRna Bioconductor library , 2011, BMC Genomics.

[21]  Gary D. Bader,et al.  GeneMANIA Cytoscape plugin: fast gene function predictions on the desktop , 2010, Bioinform..

[22]  Hai Yan,et al.  Isocitrate dehydrogenase 1 and 2 mutations in cancer: alterations at a crossroads of cellular metabolism. , 2010, Journal of the National Cancer Institute.

[23]  J. Vilo,et al.  A Data Integration Approach to Mapping OCT4 Gene Regulatory Networks Operative in Embryonic Stem Cells and Embryonal Carcinoma Cells , 2010, PloS one.

[24]  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.

[25]  James Zijun Wang,et al.  Effectively Integrating Information Content and Structural Relationship to Improve the GO-based Similarity Measure Between Proteins , 2010, BIOCOMP.

[26]  Sho Fujisawa,et al.  Nuclear CDKs Drive Smad Transcriptional Activation and Turnover in BMP and TGF-β Pathways , 2009, Cell.

[27]  K. Hoang-Xuan,et al.  Isocitrate dehydrogenase 1 codon 132 mutation is an important prognostic biomarker in gliomas. , 2009, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

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

[29]  C. Wijmenga,et al.  Using genome‐wide pathway analysis to unravel the etiology of complex diseases , 2009, Genetic epidemiology.

[30]  G. Ferbeyre,et al.  Mitochondrial Dysfunction Contributes to Oncogene-Induced Senescence , 2009, Molecular and Cellular Biology.

[31]  J. Campisi,et al.  Persistent DNA damage signaling triggers senescence-associated inflammatory cytokine secretion , 2009, Nature Cell Biology.

[32]  X. Wu,et al.  CORNA: testing gene lists for regulation by microRNAs , 2009, Bioinform..

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

[34]  Judith Campisi,et al.  Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor , 2008, PLoS biology.

[35]  L. Klein-Hitpass,et al.  The first five years of the Wnt targetome. , 2008, Cellular signalling.

[36]  Catia Pesquita,et al.  Metrics for GO based protein semantic similarity: a systematic evaluation , 2008, BMC Bioinformatics.

[37]  Rob Pieters,et al.  FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to γ-secretase inhibitors , 2007, The Journal of experimental medicine.

[38]  A. Ferrando,et al.  The SCFFBW7 ubiquitin ligase complex as a tumor suppressor in T cell leukemia , 2007, The Journal of experimental medicine.

[39]  M. Blasco,et al.  Cellular Senescence in Cancer and Aging , 2007, Cell.

[40]  J. Davis Bioinformatics and Computational Biology Solutions Using R and Bioconductor , 2007 .

[41]  Francis S Collins,et al.  Mapping the cancer genome. Pinpointing the genes involved in cancer will help chart a new course across the complex landscape of human malignancies. , 2007, Scientific American.

[42]  Robert Gentleman,et al.  Using GOstats to test gene lists for GO term association , 2007, Bioinform..

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

[44]  S. Lowe,et al.  A Novel Role for High-Mobility Group A Proteins in Cellular Senescence and Heterochromatin Formation , 2006, Cell.

[45]  Stijn van Dongen,et al.  miRBase: microRNA sequences, targets and gene nomenclature , 2005, Nucleic Acids Res..

[46]  Lincoln Stein,et al.  Reactome: a knowledgebase of biological pathways , 2004, Nucleic Acids Res..

[47]  G. Maira,et al.  Extensive modulation of a set of microRNAs in primary glioblastoma. , 2005, Biochemical and biophysical research communications.

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

[49]  Gordon K. Smyth,et al.  limma: Linear Models for Microarray Data , 2005 .

[50]  Olivier Bodenreider,et al.  Ontology-driven similarity approaches to supporting gene func- tional assessment , 2005 .

[51]  Andrew P. Weng,et al.  Activating Mutations of NOTCH1 in Human T Cell Acute Lymphoblastic Leukemia , 2004, Science.

[52]  Jean YH Yang,et al.  Bioconductor: open software development for computational biology and bioinformatics , 2004, Genome Biology.

[53]  P. Shannon,et al.  Cytoscape: a software environment for integrated models of biomolecular interaction networks. , 2003, Genome research.

[54]  S. Lowe,et al.  Rb-Mediated Heterochromatin Formation and Silencing of E2F Target Genes during Cellular Senescence , 2003, Cell.

[55]  T. Hunter,et al.  Evolution of protein kinase signaling from yeast to man. , 2002, Trends in biochemical sciences.

[56]  H. Brantjes,et al.  TCF: Lady Justice Casting the Final Verdict on the Outcome of Wnt Signalling , 2002, Biological chemistry.

[57]  J. Massagué,et al.  The nuclear import function of Smad2 is masked by SARA and unmasked by TGFb-dependent phosphorylation , 2000, Nature Cell Biology.

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

[59]  M. Ashburner,et al.  Gene Ontology: tool for the unification of biology , 2000, Nature Genetics.

[60]  R. Evans,et al.  A histone deacetylase corepressor complex regulates the Notch signal transduction pathway. , 1998, Genes & development.

[61]  D. Anderson,et al.  Reactive oxygen species-induced DNA damage and its modification: a chemical investigation. , 1997, Mutation research.

[62]  Philip Resnik,et al.  Using Information Content to Evaluate Semantic Similarity in a Taxonomy , 1995, IJCAI.

[63]  J. Trent,et al.  WAF1, a potential mediator of p53 tumor suppression , 1993, Cell.

[64]  Robin C. Allshire,et al.  Telomere reduction in human colorectal carcinoma and with ageing , 1990, Nature.

[65]  C. Harley,et al.  Telomeres shorten during ageing of human fibroblasts , 1990, Nature.