Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma: possible link to acquired resistance to anti-VEGF therapy.
Hypoxia suppresses cylindromatosis (CYLD) expression to promote inflammation in glioblastoma: possible link to acquired resistance to anti-VEGF therapy.
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DOI：
10.18632/oncotarget.2216
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发表时间：
2014-08-15
期刊：
影响因子：
--
通讯作者：
Jono H
中科院分区：
文献类型：
--
作者：
Guo J;Shinriki S;Su Y;Nakamura T;Hayashi M;Tsuda Y;Murakami Y;Tasaki M;Hide T;Takezaki T;Kuratsu J;Yamashita S;Ueda M;Li JD;Ando Y;Jono H
Cylindromatsis(CyLD)是一种肿瘤抑制因子，通过作为脱泛素酶调节信号通路。在多种恶性肿瘤中，细胞色素D脱氢酶表达下调，具有促肿瘤作用。尽管我们在侵袭性最强的脑肿瘤--人类多形性胶质母细胞瘤(GBM)缺氧区发现了CyLD的表达缺失，但其在GBM中的生物学作用尚不清楚。本研究旨在确定CyLD下调对GBM进展和治疗的生物学意义。在低氧的GBM细胞中，CyLD mRNA转录显著下调，这与我们对人GBM组织的临床观察一致。低氧增强了基础和肿瘤坏死因子-α诱导的各种致炎细胞因子的表达，而CyLD的过度表达强烈地抵消了这些反应。此外，使用贝伐单抗(一种抗血管内皮生长因子(VEGF)抗体)进行慢性抗血管生成治疗，并加强低氧，在异种移植小鼠模型中产生的反应类似于CyLD调节的促炎反应。组织学上，CyLD明显阻止了坏死区周围大量免疫细胞的渗透，在贝伐单抗治疗的对照肿瘤中出现了假扁桃体。此外，CyLD的过度表达本身对生存没有影响，显著提高了贝伐单抗的生存效果。这些数据表明，CyLD的下调在低氧介导的基底膜炎症中起着关键作用，这可能会影响抗血管内皮生长因子治疗的长期疗效。
Cylindromatosis (CYLD) is a tumor suppressor that regulates signaling pathways by acting as a deubiquitinating enzyme. CYLDdown-regulation occurred in several malignancies, with tumor-promoting effects. Although we found loss of CYLD expression in hypoxic regions of human glioblastoma multiforme (GBM), the most aggressive brain tumor, biological roles of CYLD in GBM remain unknown. This study aimed to determine the biological significance of CYLD down-regulation to GBM progression and therapy. CYLD mRNA transcription was dramatically down-regulated in hypoxic GBM cells, consistent with our clinical observations of human GBM tissues. Hypoxia enhanced both basal and tumor necrosis factor-α-induced expression of various proinflammatory cytokines, whereas CYLD overexpression strongly counteracted these responses. In addition, chronic anti-angiogenic therapy with bevacizumab, an anti-vascular endothelial growth factor (VEGF) antibody, with enhanced hypoxia produced responses similar to these CYLD-regulated proinflammatory responses in a xenograft mouse model. Histologically, CYLD clearly prevented massive immune cell infiltration surrounding necrotic regions, and pseudopalisades appeared in bevacizumab-treated control tumors. Furthermore, CYLD overexpression, which had no impact on survival by itself, significantly improved the prosurvival effect of bevacizumab. These data suggest that CYLD down-regulation is crucial for hypoxia-mediated inflammation in GBM, which may affect the long-term efficacy of anti-VEGF therapy.
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DOI：
10.1084/jem.20082044
发表时间：
2009-01-16
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Massoumi R;Kuphal S;Hellerbrand C;Haas B;Wild P;Spruss T;Pfeifer A;Fässler R;Bosserhoff AK
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影响因子：
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DOI：
10.1158/1078-0432.ccr-12-1281
发表时间：
2013-04-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Jahangiri A;De Lay M;Miller LM;Carbonell WS;Hu YL;Lu K;Tom MW;Paquette J;Tokuyasu TA;Tsao S;Marshall R;Perry A;Bjorgan KM;Chaumeil MM;Ronen SM;Bergers G;Aghi MK
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