title: Transcriptional network analysis reveals that AT1 and AT2 angiotensin II receptors are both involved in the regulation of genes essential for glioma progression.
abstract: Gliomas are aggressive primary brain tumors with high infiltrative potential. The expression of Angiotensin II (Ang II) receptors has been associated with poor prognosis in human astrocytomas, the most common type of glioma. In this study, we investigated the role of Angiotensin II in glioma malignancy through transcriptional profiling and network analysis of cultured C6 rat glioma cells exposed to Ang II and to inhibitors of its membrane receptor subtypes. C6 cells were treated with Ang II and specific antagonists of AT1 and AT2 receptors. Total RNA was isolated after three and six hours of Ang II treatment and analyzed by oligonucleotide microarray technology. Gene expression data was evaluated through transcriptional network modeling to identify how differentially expressed (DE) genes are connected to each other. Moreover, other genes co-expressing with the DE genes were considered in these analyses in order to support the identification of enriched functions and pathways. A hub-based network analysis showed that the most connected nodes in Ang II-related networks exert functions associated with cell proliferation, migration and invasion, key aspects for glioma progression. The subsequent functional enrichment analysis of these central genes highlighted their participation in signaling pathways that are frequently deregulated in gliomas such as ErbB, MAPK and p53. Noteworthy, either AT1 or AT2 inhibitions were able to down-regulate different sets of hub genes involved in protumoral functions, suggesting that both Ang II receptors could be therapeutic targets for intervention in glioma. Taken together, our results point out multiple actions of Ang II in glioma pathogenesis and reveal the participation of both Ang II receptors in the regulation of genes relevant for glioma progression. This study is the first one to provide systems-level molecular data for better understanding the protumoral effects of Ang II in the proliferative and infiltrative behavior of gliomas.
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Hátylas
authors.initials: H
authors.lastname: Azevedo
authors.affiliation: Department of Computer Science, Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, SP, Brazil.
authors.forename: André
authors.initials: A
authors.lastname: Fujita
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Silvia Yumi
authors.initials: SY
authors.lastname: Bando
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Priscila
authors.initials: P
authors.lastname: Iamashita
authors.affiliation: Department of Pediatrics, Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo, SP, Brazil.
authors.forename: Carlos Alberto
authors.initials: CA
authors.lastname: Moreira-Filho
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D019295:Computational Biology; D018450:Disease Progression; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D020043:Genes, Essential; D005910:Glioma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D044140:Receptor, Angiotensin, Type 1 / Q000235:genetics*; D044139:Receptor, Angiotensin, Type 2 / Q000235:genetics*; D015203:Reproducibility of Results; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D059467:Transcriptome
chemical_list: D044140:Receptor, Angiotensin, Type 1; D044139:Receptor, Angiotensin, Type 2; D014157:Transcription Factors