Dataset Information

Inhibition of Proliferation by Knockdown of Transmembrane (TMEM) 168 in Glioblastoma Cells via Suppression of Wnt/?-Catenin Pathway.

ABSTRACT: Human glioblastoma multiforme (GBM) accounts for the majority of human brain gliomas. Several TMEM proteins, such as TMEM 45A, TMEM 97, and TMEM 140, are implicated in human brain gliomas. However, the roles of TMEM168 in human GBM remain poorly understood. Herein we found that mRNA levels of TMEM168 were overexpressed in GBM patients (n?=?85) when compared with healthy people (n?=?10), which was also supported by data from The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis of Gene Expression Omnibus dataset GSE16011 suggested that enhanced TMEM168 expression was associated with shorter survival time. To investigate whether and how TMEM168 functioned in the tumorigenesis of human GBM cells, two human GBM cell lines (U87 and U373) were used for study. Lithium chloride (LiCl), an activator for Wnt/?-catenin pathway, was used for the treatment. Our data suggested that siRNA-TMEM168 (siTMEM168) prevented viability of U87 and U373 cells, induced cell cycle arrest (G₀/G₁ phase) and promoted apoptosis, and the mechanisms involved in blocking Wnt/?-catenin pathway, as evidenced by reducing expression of ?-catenin, C-myc, cyclin D1, and survivin. Furthermore, the inhibited effect of siTMEM168 on human GBM cell growth was significantly alleviated with additional LiCl treatment, substantiating the involvement of the Wnt/?-catenin pathway in this process. In summary, our data demonstrated that TMEM168 may represent a therapeutic target for the treatment of human GBM.

SUBMITTER: Xu J

PROVIDER: S-EPMC7848296 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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Inhibition of Proliferation by Knockdown of Transmembrane (TMEM) 168 in Glioblastoma Cells via Suppression of Wnt/β-Catenin Pathway.

Xu Jie J Su Zhongzhou Z Ding Qiuping Q Shen Liang L Nie Xiaohu X Pan Xuyan X Yan Ai A Yan Renfu R Zhou Yue Y Li Liqin L Lu Bin B

Oncology research 20190325 7

Human glioblastoma multiforme (GBM) accounts for the majority of human brain gliomas. Several TMEM proteins, such as TMEM 45A, TMEM 97, and TMEM 140, are implicated in human brain gliomas. However, the roles of TMEM168 in human GBM remain poorly understood. Herein we found that mRNA levels of TMEM168 were overexpressed in GBM patients (<i>n</i> = 85) when compared with healthy people (<i>n</i> = 10), which was also supported by data from The Cancer Genome Atlas (TCGA). Kaplan-Meier analysis of G ...[more]

PMID: 30940290

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Project description:Background:Mishandling of intracellular chloride (Cl-) concentration ([Cl-]i) in cerebrovascular smooth muscle cells is implicated in several pathological processes, including hyperplasia and remodeling. We investigated the effects of ClC-2-mediated Cl- efflux on the proliferation of human brain vascular smooth muscle cells (HBVSMCs) induced by angiotensin II (AngII). Methods:Cell proliferation and motility were determined using the CCK-8, bromodeoxyuridine staining, wound healing and invasion assays. ClC-2, PCNA, Ki67, survivin and cyclin D1 expression, and ?-catenin and GSK-3? phosphorylation were examined using western blotting. Histological analyses were performed using hematoxylin and eosin staining and ?-SMA staining. Results:Our results showed that AngII-induced HBVSMC proliferation was accompanied by a decrease in [Cl-]i and an increase in ClC-2 expression. Inhibition of ClC-2 by siRNA prevented AngII from inducing the efflux of Cl-. AngII-induced HBVSMC proliferation, migration and invasion were significantly attenuated by ClC-2 downregulation. The inhibitory effects of ClC-2 knockout on HBVSMC proliferation and motility were associated with inactivation of the Wnt/?-catenin signaling pathway, as evidenced by inhibition of ?-catenin phosphorylation and nuclear translocation, and decrease of GSK-3? phosphorylation and survivin and cyclin D1 expression. Recombinant Wnt3a treatment markedly reversed the effect of ClC-2 knockdown on HBVSMC viability. An in vivo study revealed that knockdown of ClC-2 with shRNA adenovirus ameliorated basilar artery remodeling by inhibiting Wnt/?-catenin signaling in AngII-treated mice. Conclusion:This study demonstrates that blocking ClC-2-mediated Cl- efflux inhibits AngII-induced cerebrovascular smooth muscle cell proliferation and migration by inhibiting the Wnt/?-catenin pathway. Our data indicate that downregulation of ClC-2 may be a viable strategy in the prevention of hyperplasia and remodeling of cerebrovascular smooth muscle cells.

Dataset Information

Inhibition of Proliferation by Knockdown of Transmembrane (TMEM) 168 in Glioblastoma Cells via Suppression of Wnt/?-Catenin Pathway.

Publications

Inhibition of Proliferation by Knockdown of Transmembrane (TMEM) 168 in Glioblastoma Cells via Suppression of Wnt/β-Catenin Pathway.

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