Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells
Tetraspanin CD9 stabilizes gp130 by preventing its ubiquitin-dependent lysosomal degradation to promote STAT3 activation in glioma stem cells
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DOI：
10.1038/cdd.2016.110
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发表时间：
2017-01-01
影响因子：
12.4
通讯作者：
Bao, Shideng
中科院分区：
文献类型：
--
作者：
Shi, Yu;Zhou, Wenchao;Bao, Shideng
胶质母细胞瘤（GBM）是最恶性和致命的脑肿瘤，其含有促进肿瘤增殖和治疗抗性的胶质瘤干细胞（GSC）。GSC优先表达几种关键的细胞表面分子，其调节促存活信号以维持干细胞样表型。四跨膜蛋白CD 9最近被报道为与GSC维持相关的GSC生物标志物。然而，CD 9维持GSC特性的潜在分子机制仍然难以捉摸。在此，我们报告CD 9通过阻止其遍在蛋白依赖性溶酶体降解来稳定IL-6受体糖蛋白130（gp 130），以促进GSC中的STAT 3激活。CD 9优先在人GBM肿瘤的GSC中表达。质谱分析鉴定gp 130为GSC中CD 9的相互作用蛋白，免疫沉淀和免疫荧光分析证实了这一点。通过shRNA阻断CD 9或gp 130基因表达，可显著抑制GSCs的自我更新，促进GSCs的分化。此外，CD 9破坏显著降低GSC中gp 130蛋白水平和STAT 3活化磷酸化。CD 9通过阻止其泛素依赖性溶酶体降解来稳定gp 130，以促进GSC中的BMX-STAT 3信号传导。重要的是，靶向CD 9有效地抑制了体内GSC肿瘤生长，而组成性激活的STAT 3（STAT 3-C）的异位表达恢复了因CD 9破坏而受损的肿瘤生长。总的来说，我们发现了由四跨膜蛋白CD 9介导的关键调节机制，以维持GSC的干细胞样特性和致瘤潜力。
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 pro-survival 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 ubiquitin-dependent 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.