Abstract
ObjectiveTo examine the association between fragile X mental retardation protein (FMRP) expression and astrocytoma characteristics.MethodsPathologic grade and expressions of glial fibrillary acidic protein (GFAP), Ki67 (proliferation marker), and FMRP were determined in astrocytoma specimens from 74 patients. Kaplan-Meier survival analysis was undertaken. Pathologic grade and protein levels of FMRP were determined in 24 additional patients with astrocytoma and 6 controls (cerebral trauma). In cultured U251 and U87 cell lines, the effects of FMRP knock-down on cell proliferation, AKT/mTOR/GSK-3β and MEK/ERK signaling were studied. The effects of FMRP knock-down on the volumes and weights of U251 cell-derived orthotopic tumors in mice were investigated.ResultsIn patients, FMRP expression was increased in grade IV (5.1-fold, P<0.01) and grade III (3.2-fold, P<0.05) astrocytoma, compared with controls. FMRP and Ki67 expressions were positively correlated (R2=0.877, P<0.001). Up-regulation of FMRP was associated with poorer survival among patients with FMRP integrated optical density >30 (P<0.01). In astrocytoma cell lines, FMRP knock-down slowed proliferation (P<0.05), inhibited total MEK levels P<0.05, and reduced phosphorylation of MEK (Ser217/221) and ERK (Thr202/Tyr204) (P<0.05). In mice with orthotopic tumors, FMRP knock-down decreased FMRP and Ki67 expressions, and reduced tumor volume and weight (36.3% or 61.5% on day 15, both P<0.01). Also, phosphorylation of MEK (Ser217/221) and ERK (Thr202/Tyr204), and total MEK in xenografts were decreased in sh-FMRP xenografts compared with non-transfected ones (all P<0.05).ConclusionEnhanced FMRP expression in astrocytoma may promote proliferation through activation of MEK/ERK signaling.
Highlights
Gliomas are the most common type of primary brain tumors, accounting for approximately 80% of all malignant intracranial tumors [1]
Phosphorylation of mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK) (Ser217/221) and ERK (Thr202/Tyr204), and total MEK in xenografts were decreased in sh-Fragile X mental retardation protein (FMRP) xenografts compared with non-transfected ones
The detailed mechanisms underlying the phenotype in Fragile X syndrome (FXS) remain to be characterized, it has been reported that the absence of FMRP may lead to dysregulation of MEK/ERK and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin/glycogen synthase kinase-3-beta (GSK-3β) signaling pathways [14,15,16,17]
Summary
Gliomas are the most common type of primary brain tumors, accounting for approximately 80% of all malignant intracranial tumors [1]. They are a relatively rare form of tumor (an overall age-adjusted incidence rate of 4.67 to 5.73 per 100,000 persons), gliomas are associated with significant morbidity and mortality [1]. Constitutive activation of the mitogen-activated protein kinase/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling pathway has been reported to promote the proliferation and migration of glioma cells [6]. Fragile X syndrome (FXS) is a monogenic disease that is associated with the expansion of the CGG trinucleotide repeat in the Fragile X mental retardation-1 (FMR1) gene, resulting in a failure to express the Fragile X mental retardation protein (FMRP). The detailed mechanisms underlying the phenotype in FXS remain to be characterized, it has been reported that the absence of FMRP may lead to dysregulation of MEK/ERK and phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR)/glycogen synthase kinase-3-beta (GSK-3β) signaling pathways [14,15,16,17]
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