Yuanyuan Chen1, Delong Meng1, Huibo Wang1, Ruochuan Sun1, Dongrui Wang1, Shuai Wang1, Jiajun Fan1, Yingjie Zhao1, Jingkun Wang1, Song Yang1, Cong Huai1, Xiao Song1, Rong Qin1, Tao Xu1, Dapeng Yun1, Lingna Hu1, Jingmin Yang1, Xiaotian Zhang1, Haoming Chen1, Juxiang Chen1, Hongyan Chen1, Daru Lu1. 1. State Key Laboratory of Genetic Engineering and MOE Key Laboratory of Contemporary Anthropology, School of Life Sciences, Shanghai, China (Y.C., D.M., D.W., Y.Z., J.W., C.H., X.S., D.Y., L.H., J.Y., H.C., H.C., D.L.); Department of Biosynthesis, School of Pharmacy, Fudan University, Shanghai, China (J.F.); Department of Neurosurgery, (H.W.); Department of Hematology, First Affiliated Hospital of Nanjing Medical University, Nanjing, China (S.W.); Eighth Department of General Surgery and Department of Pathology, First Affiliated Hospital of Anhui Medical University, Hefei, China (R.S., S.Y.); Department of Molecular Human Genetics, Baylor College of Medicine, Houston, Texas (X.Z.); Neurosurgery Research Institution of Shanghai, Department of Neurosurgery, Changzheng Hospital, Second Military Medical University, Shanghai, China (R.Q., T.X., J.C.).
Abstract
BACKGROUND: Malignant glioma is a common and lethal primary brain tumor in adults. Here we identified a novel oncoprotein, vesicle-associated membrane protein 8 (VAMP8), and investigated its roles in tumorigenisis and chemoresistance in glioma. METHODS: The expression of gene and protein were determined by quantitative PCR and Western blot, respectively. Histological analysis of 282 glioma samples and 12 normal controls was performed by Pearson's chi-squared test. Survival analysis was performed using the log-rank test and Cox proportional hazards regression. Cell proliferation and cytotoxicity assay were conducted using Cell Counting Kit-8. Autophagy was detected by confocal microscopy and Western blot. RESULTS: VAMP8 was significantly overexpressed in human glioma specimens and could become a potential novel prognostic and treatment-predictive marker for glioma patients. Overexpression of VAMP8 promoted cell proliferation in vitro and in vivo, whereas knockdown of VAMP8 attenuated glioma growth by arresting cell cycle in the G0/G1 phase. Moreover, VAMP8 contributed to temozolomide (TMZ) resistance by elevating the expression levels of autophagy proteins and the number of autophagosomes. Further inhibition of autophagy via siRNA-mediated knockdown of autophagy-related gene 5 (ATG5) or syntaxin 17 (STX17) reversed TMZ resistance in VAMP8-overexpressing cells, while silencing of VAMP8 impaired the autophagic flux and alleviated TMZ resistance in glioma cells. CONCLUSION: Our findings identified VAMP8 as a novel oncogene by promoting cell proliferation and therapeutic resistance in glioma. Targeting VAMP8 may serve as a potential therapeutic regimen for the treatment of glioma.
BACKGROUND:Malignant glioma is a common and lethal primary brain tumor in adults. Here we identified a novel oncoprotein, vesicle-associated membrane protein 8 (VAMP8), and investigated its roles in tumorigenisis and chemoresistance in glioma. METHODS: The expression of gene and protein were determined by quantitative PCR and Western blot, respectively. Histological analysis of 282 glioma samples and 12 normal controls was performed by Pearson's chi-squared test. Survival analysis was performed using the log-rank test and Cox proportional hazards regression. Cell proliferation and cytotoxicity assay were conducted using Cell Counting Kit-8. Autophagy was detected by confocal microscopy and Western blot. RESULTS:VAMP8 was significantly overexpressed in humanglioma specimens and could become a potential novel prognostic and treatment-predictive marker for gliomapatients. Overexpression of VAMP8 promoted cell proliferation in vitro and in vivo, whereas knockdown of VAMP8attenuated glioma growth by arresting cell cycle in the G0/G1 phase. Moreover, VAMP8 contributed to temozolomide (TMZ) resistance by elevating the expression levels of autophagy proteins and the number of autophagosomes. Further inhibition of autophagy via siRNA-mediated knockdown of autophagy-related gene 5 (ATG5) or syntaxin 17 (STX17) reversed TMZ resistance in VAMP8-overexpressing cells, while silencing of VAMP8 impaired the autophagic flux and alleviated TMZ resistance in glioma cells. CONCLUSION: Our findings identified VAMP8 as a novel oncogene by promoting cell proliferation and therapeutic resistance in glioma. Targeting VAMP8 may serve as a potential therapeutic regimen for the treatment of glioma.
Authors: Ping Zhao; Lu Yang; Jamie A Lopez; Junmei Fan; James G Burchfield; Li Bai; Wanjin Hong; Tao Xu; David E James Journal: J Cell Sci Date: 2009-10-01 Impact factor: 5.285
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