Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells

Abstract

Glioblastoma (GBM) is the most malignant and lethal brain tumor harboring glioma stem cells (GSCs) that promote tumor propagation and therapeutic resistance. GSCs preferentially express several critical cell surface molecules that regulate the prosurvival signaling for maintaining the stem cell-like phenotype. Tetraspanin CD9 has recently been reported as a GSC biomarker that is relevant to the GSC maintenance. However, the underlying molecular mechanisms of CD9 in maintaining GSC property remain elusive. Herein, we report that CD9 stabilizes the IL-6 receptor glycoprotein 130 (gp130) by preventing its ubiquitindependent lysosomal degradation to facilitate the STAT3 activation in GSCs. CD9 is preferentially expressed in GSCs of human GBM tumors. Mass spectrometry analysis identified gp130 as an interacting protein of CD9 in GSCs, which was confirmed by immunoprecipitation and immunofluorescent analyses. Disrupting CD9 or gp130 by shRNA significantly inhibited the self-renewal and promoted the differentiation of GSCs. Moreover, CD9 disruption markedly reduced gp130 protein levels and STAT3 activating phosphorylation in GSCs. CD9 stabilized gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote the BMX-STAT3 signaling in GSCs. Importantly, targeting CD9 potently inhibited GSC tumor growth in vivo, while ectopic expression of the constitutively activated STAT3 (STAT3-C) restored the tumor growth impaired by CD9 disruption. Collectively, we uncovered a critical regulatory mechanism mediated by tetraspanin CD9 to maintain the stem cell-like property and tumorigenic potential of GSCs.

The protective effect of WKYMVm peptide on inflammatory osteolysis through regulating NF‐κB and CD9/gp130/STAT3 signalling pathway

“…Additionally, during the exploration of the underlying mechanism, we found that WKYMVm suppresses osteoclastogenesis directly through NF-κB and STAT3 and indirectly through CD9/ gp130/STAT3. 24 Based on these findings, we have been suggested that inhibition of CD9 expression may also interfere with the IL6/gp130/STAT3 pathway under inflammatory conditions to alter osteoclastogenesis behaviour. NF-κB promotes the nuclear translocation of NFATc1 and c-Fos, leading ultimately to osteoclastogenesis.…”

“…12,13 The role of monocyte/macrophage lineage cell-cell fusion for the process of osteoclastogenesis should not be neglected, because it lays a foundation for the eventual osteoclast maturation. [21][22][23][24] These data imply that the inhibition of CD9 expression can indirectly impact IL-6/gp130/STAT3 activation, which can serve as a new strategy for altering osteoclast behaviour under inflammatory conditions. Moreover, in patients with Paget's disease, a variant of the DC-STAMP gene-promoting osteoclastogenesis has been identified.…”

Integrative transcriptomic and proteomic analysis reveals CD9/ITGA4/PI3K‐Akt axis mediates trabecular meshwork cell apoptosis in human glaucoma

“…Disruption of CD9 can significantly inhibit the self‐renewal and promoted the differentiation of GSCs. CD9 disruption markedly reduced gp130 protein levels and STAT3 activating phosphorylation in GSCs . Moreover, studies found that CD9 is high associated with PI3K activity.…”

Neutralizing gp130 interferes with endothelial-mediated effects on glioblastoma stem-like cells

“…In this article, the authors implicate the glycoprotein gp130 and the tetraspanin CD9 as vital to maintaining the stem-like characteristics of GSCs. 6 Employing RNA interference techniques, they observed a reduction in the stem-like properties of GSCs in the absence of gp130 when cultured in complete media. 6 Our laboratory has also explored the role of gp130 in GSCs, using neutralizing antibodies (B-K5 clone) to pharmacologically alter its functions.…”

“…6 Employing RNA interference techniques, they observed a reduction in the stem-like properties of GSCs in the absence of gp130 when cultured in complete media. 6 Our laboratory has also explored the role of gp130 in GSCs, using neutralizing antibodies (B-K5 clone) to pharmacologically alter its functions. To better reflect the in vivo endothelial microenvironment, our study was performed in human brain endothelial cell-conditioned serum-free mitogen-free media (EC-CM).…”