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.
Highlights
The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis, and its overall survival is quite low (6–12 months) [1]
We found that tetraspanin 8 (Tspan8) is over-expressed in human malignant glioma tissues, as well as in several human glioma cell lines
Through Western blot, we examined the expression of Tspan8 in human malignant gliomas
Summary
The malignant glioma remains one of the most aggressive human malignancies with extremely poor prognosis, and its overall survival is quite low (6–12 months) [1]. Tumor cell infiltration and local invasion remain the overwhelming causes of death for malignant glioma cancer patients. Tetraspanins, a family of four transmembrane proteins, were shown to physically associate with a large variety of transmembrane and/or cytosolic proteins, and regulate many important cellular functions, such as cell migration, adhesion, invasion and proliferation [5,6,7]. Tetraspanins, in complex with various integrins, are important for integrin compartmentalization, internalization, recycling and signaling, as well as cell spreading, migration and local invasion [8,9,10]. Several tetraspanins are over-expressed in many cancers, and are often associated with poor prognosis [11,12]. High Tspan expression in colorectal cancer often indicate poor prognosis [15]. Over-expressed Tspan forms a complex with rictor and integrin α3, which is required for mTORC2 activation and glioma cell migration
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