High TGFbeta-Smad activity confers poor prognosis in glioma patients and promotes cell proliferation depending on the methylation of the PDGF-B gene.
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.
Bruna
Alejandra
A
Medical Oncology Program, Vall d'Hebron University Hospital Research Institute, 08035 Barcelona, Spain.
Darken
Rachel S
RS
Rojo
Federico
F
Ocaña
Alberto
A
Peñuelas
Silvia
S
Arias
Alexandra
A
Paris
Raquel
R
Tortosa
Avelina
A
Mora
Jaume
J
Baselga
Jose
J
Seoane
Joan
J
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
D020574:Proto-Oncogene Proteins c-sis; D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta