EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway.
EGFRvIII promotes glioma angiogenesis and growth through the NF-κB, interleukin-8 pathway.
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DOI：
10.1038/onc.2011.563
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发表时间：
2012-09-06
期刊：
影响因子：
8
通讯作者：
Furnari, F. B.
中科院分区：
文献类型：
--
作者：
Bonavia, R.;Inda, M. M.;Vandenberg, S.;Cheng, S-Y;Nagane, M.;Hadwiger, P.;Tan, P.;Sah, D. W. Y.;Cavenee, W. K.;Furnari, F. B.
维持高增长率需要肿瘤利用其微环境中的资源。这方面的一个例子是广泛的血管生成，这是高级别胶质瘤的典型特征。在这里，我们表明，成分活性突变的表皮生长因子受体ΔEGFR(EGFRvIII，EGFR*，de2-7EGFR)的表达与人胶质瘤标本和胶质瘤干细胞中促血管生成因子IL-8的表达水平显著升高有关。此外，Δ表皮生长因子受体在不同的胶质瘤细胞系中的异位表达导致IL-8的分泌增加了60倍。这些细胞的异种移植表现出新生血管的增加，这不是由细胞过度表达野生型(Wt)表皮生长因子受体或Δ表皮生长因子受体伴随额外的激酶域突变所引起的。对IL-8启动子定点突变的分析表明，ΔEGFR通过转录因子-κB、激活蛋白1(AP-1)和CCAAT/增强子结合蛋白(C/EBP)调节IL-8的表达。高表达ΔEGFR的胶质瘤细胞表现为核因子-κB的结构性激活和DNA结合，c-jun及其上游激酶c-jun氨基末端激酶的高表达和C/EBPβ的高表达。选择性的药物或基因靶向的NF-κB或AP-1通路有效地阻断了启动子的活性和IL-8的分泌。此外，RNAi介导的IL-8或NF-κB亚单位p65在ΔEGFR表达细胞中的下调，当注射到裸鼠皮下时，减弱了它们形成肿瘤和诱导血管生成的能力。相反，在缺乏ΔEGFR的胶质瘤细胞中过表达IL-8可以有效地增强其成瘤性，并产生高度血管化的肿瘤，提示该细胞因子及其转录调节因子在促进胶质瘤血管生成和肿瘤生长中的重要性。
Sustaining a high growth rate requires tumors to exploit resources in their microenvironment. One example of this is the extensive angiogenesis that is a typical feature of high-grade gliomas. Here, we show that expression of the constitutively active mutant epidermal growth factor receptor, ΔEGFR (EGFRvIII, EGFR*, de2-7EGFR) is associated with significantly higher expression levels of the pro-angiogenic factor interleukin (IL)-8 in human glioma specimens and glioma stem cells. Furthermore, the ectopic expression of ΔEGFR in different glioma cell lines caused up to 60-fold increases in the secretion of IL-8. Xenografts of these cells exhibit increased neovascularization, which is not elicited by cells overexpressing wildtype (wt)EGFR or ΔEGFR with an additional kinase domain mutation. Analysis of the regulation of IL-8 by site-directed mutagenesis of its promoter showed that ΔEGFR regulates its expression through the transcription factors nuclear factor (NF)-κB, activator protein 1 (AP-1) and CCAAT/enhancer binding protein (C/EBP). Glioma cells overexpressing ΔEGFR showed constitutive activation and DNA binding of NF-κB, overexpression of c-Jun and activation of its upstream kinase c-Jun N-terminal kinase (JNK) and overexpression of C/EBPβ. Selective pharmacological or genetic targeting of the NF-κB or AP-1 pathways efficiently blocked promoter activity and secretion of IL-8. Moreover, RNA interference-mediated knock-down of either IL-8 or the NF-κB subunit p65, in ΔEGFR-expressing cells attenuated their ability to form tumors and to induce angiogenesis when injected subcutaneously into nude mice. On the contrary, the overexpression of IL-8 in glioma cells lacking ΔEGFR potently enhanced their tumorigenicity and produced highly vascularized tumors, suggesting the importance of this cytokine and its transcription regulators in promoting glioma angiogenesis and tumor growth.
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影响因子：
10.5
作者：
Inda, Maria-del-Mar;Bonavia, Rudy;Furnari, Frank
通讯作者：
Furnari, Frank
影响因子：
4.8
作者：
Antonyak, MA;Moscatello, DK;Wong, AJ
通讯作者：
Wong, AJ
影响因子：
64.8
作者：
Garkavtsev, I;Kozin, SV;Jain, RK
通讯作者：
Jain, RK
影响因子：
50.3
作者：
Bachoo, RM;Maher, EA;DePinho, RA
通讯作者：
DePinho, RA
影响因子：
8.8
作者：
Jaros, E;Perry, R H;Adam, L;Kelly, P J;Crawford, P J;Kalbag, R M;Mendelow, A D;Sengupta, R P;Pearson, A D
通讯作者：
Pearson, A D