Fragile X mental retardation protein promotes astrocytoma proliferation via the MEK/ERK signaling pathway

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.

Importance of GFAP isoform‐specific analyses in astrocytoma

“…Quantification of differences in GFAP expression between astrocytoma grades was not performed in the studies listed in Table . Nevertheless, the observation of a decreasing number of GFAP positive cells with increasing astrocytoma grade is frequently mentioned (Cras et al, ; Cruz‐Sanchez et al, ; Gullotta et al, ; Oh & Prayson, ; Royds et al, ; van der Meulen et al, ; Xing et al, ). One of the studies, however, describes stronger staining of GFAP in grade III compared to lower grade astrocytoma (Cruz‐Sanchez et al, ).…”

The Fragile X Mental Retardation Protein Regulates RIPK1 and Colorectal Cancer Resistance to Necroptosis

“… 6 , 7 The fragile X mental retardation protein (FMRP), a RBP involved in multiple steps of mRNA metabolism, is gaining a pivotal importance in controlling the development and growth of different types of human cancer. 8 , 9 , 10 Mutations or absence of FMRP cause fragile X syndrome (FXS), the most frequent form of inherited intellectual disability in humans. 11 In brain, the absence of FMRP causes impaired structural and functional synaptic plasticity partially due to defects in locally synthesized proteins, cytoskeletal organization, and receptor mobility.…”

Bone marrow‐derived cells response in proximal regions of nerves after peripheral nerve injury

“…Nuclei were counterstained with 4′,6‐diamidino‐2‐phenylindole (DAPI; 1:500, Invitrogen) for 30 s. The sections were mounted on slides using a fluorescence mounting medium (Dako, USA), and fluorescent images were obtained with a confocal microscope (Leica SP5, Germany). The intensities of immunofluorescence staining were quantified by calculating the integrated optical density (IOD) of positive expression from six random sections using Image‐Pro Plus 6.0 software (Media Cybernetics, USA) as described elsewhere (Jing et al, ; Xing et al, ).…”