Fragile X mental retardation protein promotes astrocytoma proliferation via the MEK/ERK signaling pathway
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Zhou Xing1,4,*, Minling Zeng4,*, Huixian Hu2,*, Hui Zhang2, Zhuofang Hao6, Yuesheng Long5, Shengqiang Chen5, Hang Su2, Zhongmin Yuan4,5, Meng Xu1, Jingqi Chen2,3
1Department of Oncology, the First Affiliated Hospital, Jinan University, Guangzhou 510632, People's Republic of China
2Translational Medicine Center, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, People's Republic of China
3Department of Medical Oncology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, People's Republic of China
4Department of Neurosurgery, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, People's Republic of China
5Institute of Neuroscience; Key Laboratory of Neurogenetics and Channelopathies of Guangdong Province and Ministry of Education of China, Guangzhou Medical University, Guangzhou 510260, People's Republic of China
6Department of Pathology, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou 510260, People's Republic of China
*These authors have contribute equally to this work
Jingqi Chen, email: [email protected]
Meng Xu, email: [email protected]
Zhongmin Yuan, email: [email protected]
Keywords: fragile X mental retardation protein, astrocytoma, MEK/ERK signaling pathway, proliferation, RNA interference
Received: January 10, 2016 Accepted: September 12, 2016 Published: September 23, 2016
Objective: To examine the association between fragile X mental retardation protein (FMRP) expression and astrocytoma characteristics.
Methods: Pathologic 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.
Results: In 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).
Conclusion: Enhanced FMRP expression in astrocytoma may promote proliferation through activation of MEK/ERK signaling.
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