title: High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene.
abstract: TGFbeta acts as a tumor suppressor in normal epithelial cells and early-stage tumors and becomes an oncogenic factor in advanced tumors. The molecular mechanisms involved in the malignant function of TGFbeta are not fully elucidated. We demonstrate that high TGFbeta-Smad activity is present in aggressive, highly proliferative gliomas and confers poor prognosis in patients with glioma. We discern the mechanisms and molecular determinants of the TGFbeta oncogenic response with a transcriptomic approach and by analyzing primary cultured patient-derived gliomas and human glioma biopsies. The TGFbeta-Smad pathway promotes proliferation through the induction of PDGF-B in gliomas with an unmethylated PDGF-B gene. The epigenetic regulation of the PDGF-B gene dictates whether TGFbeta acts as an oncogenic factor inducing PDGF-B and proliferation in human glioma.
authors.affiliation: Medical Oncology Program, Vall d'Hebron University Hospital Research Institute, 08035 Barcelona, Spain.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Bruna
authors.forename: Rachel S
authors.initials: RS
authors.lastname: Darken
authors.forename: Federico
authors.initials: F
authors.lastname: Rojo
authors.forename: Alberto
authors.initials: A
authors.lastname: Ocaña
authors.forename: Silvia
authors.initials: S
authors.lastname: Peñuelas
authors.forename: Alexandra
authors.initials: A
authors.lastname: Arias
authors.forename: Raquel
authors.initials: R
authors.lastname: Paris
authors.forename: Avelina
authors.initials: A
authors.lastname: Tortosa
authors.forename: Jaume
authors.initials: J
authors.lastname: Mora
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Joan
authors.initials: J
authors.lastname: Seoane
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001254:Astrocytoma / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology; D049109:Cell Proliferation / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D019175:DNA Methylation; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology; D005910:Glioma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007223:Infant; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011379:Prognosis; D020574:Proto-Oncogene Proteins c-sis / Q000235:genetics* / Q000378:metabolism; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism*; D051906:Smad7 Protein / Q000378:metabolism; D015996:Survival Rate; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
chemical_list: D020574:Proto-Oncogene Proteins c-sis; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta