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四跨膜蛋白8-rictor-整合素α3复合物是胶质瘤细胞迁移所必需的。

Tetraspanin 8-rictor-integrin α3 complex is required for glioma cell migration.

作者信息

Pan Si-Jian, Zhan Shi-Kun, Pan Yi-Xin, Liu Wei, Bian Liu-Guan, Sun Bomin, Sun Qing-Fang

机构信息

Department of Neurosurgery, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Shanghai Ruijin Second Road, Shanghai 200025, China.

Department of Stereotactic and Functional Neurosurgery, Rui Jin Hospital, School of Medicine, Shanghai Jiao Tong University, 197 Shanghai Ruijin Second Road, Shanghai 200025, China.

出版信息

Int J Mol Sci. 2015 Mar 9;16(3):5363-74. doi: 10.3390/ijms16035363.

DOI:10.3390/ijms16035363
PMID:25761241
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4394480/
Abstract

The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis. Glioma cell invasion and migration are the main causes of death. In the current study, we studied the expression and the potential functions of tetraspanin 8 (Tspan8) in malignant gliomas. We found that Tspan8 expression level is high in both malignant glioma tissues and in several human glioma cell lines, where it formed a complex integrin α3 and rictor, the latter is a key component of mammalian target of rapamycin (mTOR) complex 2 (mTORC2). Disruption of this complex, through siRNA-mediated knockdown of anyone of these three proteins, inhibited U251MG glioma cell migration in vitro. We further showed that Tspan8-rictor association appeared required for mTORC2 activation. Knockdown of Tspan8 by the targeted siRNAs prevented mTOR-rictor (mTORC2) assembly as well as phosphorylation of AKT (Ser-473) and protein kinase C α (PKCα) in U251MG cells. Together, these results demonstrate that over-expressed Tspan8 in malignant glioma forms a complex with rictor and integrin α3 to mediate mTORC2 activation and glioma cell migration. Therefore, targeting Tspan8-rictor-integrin α3 complex may provide a potential therapeutic intervention for malignant glioma.

摘要

恶性胶质瘤仍然是最具侵袭性的人类恶性肿瘤之一，预后极差。胶质瘤细胞的侵袭和迁移是主要的致死原因。在本研究中，我们研究了四跨膜蛋白8（Tspan8）在恶性胶质瘤中的表达及潜在功能。我们发现，Tspan8在恶性胶质瘤组织和几种人类胶质瘤细胞系中表达水平均较高，在这些细胞系中它与整合素α3和rictor形成复合物，后者是哺乳动物雷帕霉素靶蛋白（mTOR）复合物2（mTORC2）的关键组成部分。通过小干扰RNA（siRNA）介导敲低这三种蛋白中的任何一种来破坏该复合物，可在体外抑制U251MG胶质瘤细胞的迁移。我们进一步表明，Tspan8与rictor的结合似乎是mTORC2激活所必需的。用靶向siRNAs敲低Tspan8可阻止U251MG细胞中mTOR-rictor（mTORC2）的组装以及AKT（Ser-473）和蛋白激酶Cα（PKCα）的磷酸化。总之，这些结果表明，恶性胶质瘤中过表达的Tspan8与rictor和整合素α3形成复合物，介导mTORC2激活和胶质瘤细胞迁移。因此，靶向Tspan8-rictor-整合素α3复合物可能为恶性胶质瘤提供一种潜在的治疗干预手段。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/8208338e5225/ijms-16-05363-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/528d57c6b2c4/ijms-16-05363-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/27e2dcd8e4a0/ijms-16-05363-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/752271eac65b/ijms-16-05363-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/8208338e5225/ijms-16-05363-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/528d57c6b2c4/ijms-16-05363-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/27e2dcd8e4a0/ijms-16-05363-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/752271eac65b/ijms-16-05363-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/b728/4394480/8208338e5225/ijms-16-05363-g004.jpg

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