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.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
Adolescent
-
Adult
-
Aged
-
Astrocytoma / metabolism
-
Astrocytoma / pathology
-
Brain Neoplasms / metabolism
-
Brain Neoplasms / pathology
-
Cell Proliferation / drug effects*
-
Child
-
Child, Preschool
-
DNA Methylation*
-
Gene Expression Profiling
-
Gene Expression Regulation, Neoplastic
-
Glioblastoma / metabolism
-
Glioblastoma / pathology
-
Glioma / metabolism
-
Glioma / pathology*
-
Humans
-
Infant
-
Middle Aged
-
Oligonucleotide Array Sequence Analysis
-
Phosphorylation
-
Prognosis
-
Proto-Oncogene Proteins c-sis / genetics*
-
Proto-Oncogene Proteins c-sis / metabolism
-
Receptors, Transforming Growth Factor beta / metabolism
-
Signal Transduction
-
Smad2 Protein / metabolism*
-
Smad7 Protein / metabolism
-
Survival Rate
-
Transforming Growth Factor beta / pharmacology*
-
Tumor Cells, Cultured
Substances
-
Proto-Oncogene Proteins c-sis
-
Receptors, Transforming Growth Factor beta
-
Smad2 Protein
-
Smad7 Protein
-
Transforming Growth Factor beta