Epidermal growth factor receptor variant type III markedly accelerates angiogenesis and tumor growth via inducing c-myc mediated angiopoietin-like 4 expression in malignant glioma.
Epidermal growth factor receptor variant type III markedly accelerates angiogenesis and tumor growth via inducing c-myc mediated angiopoietin-like 4 expression in malignant glioma.
复制标题
DOI：
10.1186/1476-4598-12-31
复制
发表时间：
2013-04-25
期刊：
影响因子：
37.3
通讯作者：
Koizumi F
中科院分区：
文献类型：
--
作者：
Katanasaka Y;Kodera Y;Kitamura Y;Morimoto T;Tamura T;Koizumi F
组成型激活突变型EGFR变体III（EGFRvIII）是多形性胶质母细胞瘤（GBM）中最常见的突变，其表达在临床上与肿瘤增殖、侵袭和血管生成相关。在这项研究中，我们研究了EGFRvIII对肿瘤微环境的作用，特别是对血管生成的作用。为了研究EGFRvIII在肿瘤血管生成中的作用，我们制备了用增强型绿色荧光蛋白（EGFP）、野生型EGFR或EGFRvIII（LN 229-WT或-vIII）转染的LN 229胶质母细胞瘤，并检查了肿瘤中的肿瘤生长和微血管密度。此外，通过实时PCR分析鉴定潜在的血管生成因子，并检测其在LN 229-vIII细胞中的功能。在体内，与LN 229-WT细胞相比，LN 229-vIII细胞显示出更具侵袭性的肿瘤生长和更高的血管分布，尽管在体外细胞生长速率方面没有显著差异。我们接下来研究了60种血管生成相关因子的表达，以阐明LN 229-vIII和LN 229-WT的肿瘤异种移植物之间血管分布差异的潜在机制。我们发现，血管生成素样4（Angptl 4），一种参与血管生成和代谢调节的分泌蛋白的mRNA和蛋白质表达显着诱导EGFRvIII过表达，在体外和体内。使用shRNA组成型敲低LN 229-vIII中的Angptl 4显著降低了肿瘤异种移植物中的微血管密度并抑制了肿瘤生长。为了阐明EGFRvIII对Angptl 4的调控机制，我们通过药理学抑制和RNA干扰来分析信号通路和转录因子。ERK信号抑制剂U 0126显著抑制Angptl 4表达。由ERK调节的转录因子c-Myc在LN 229-vIII细胞中被激活，并且使用siRNA敲低c-Myc也减弱了LN 229-vIII细胞中的Angptl 4表达。此外，染色质免疫沉淀（ChIP）测定显示在LN 229-vIII细胞中c-Myc向Angptl 4的启动子区域的募集增加。总之，我们证明了EGFRvIII通过ERK/c-Myc途径诱导Angptl 4表达并促进恶性胶质瘤中的肿瘤血管生成。
Expression of the constitutively activated mutant EGFR variant III (EGFRvIII), the most common mutation in glioblastoma multiforme (GBMs), has been clinically correlated with tumor proliferation, invasion, and angiogenesis. In this study, we examined the role of EGFRvIII on the tumor microenvironment, especially on angiogenesis. To study the role of EGFRvIII in tumor angiogenesis, we prepared LN229 glioblastoma transfected with enhanced green fluorescent protein (EGFP), wild-type EGFR, or EGFRvIII (LN229-WT or -vIII), and examined tumor growth and microvessel density in the tumors. Additionally, the potential angiogenic factors were identified by real-time PCR analysis, and the functions in LN229-vIII cells were examined. LN229-vIII cells showed more aggressive tumor growth and higher vascularity as compared to LN229-WT cells in vivo, although there was no significant difference in the cell growth rates in vitro. We next investigated the expression of 60 angiogenesis-related factors to clarify the mechanisms underlying the difference in vascularity between tumor xenografts of LN229-vIII and LN229-WT. We found that the mRNA and protein expressions of angiopoietin-like 4 (Angptl4), a secreted protein involved in angiogenesis and metabolism regulation, were significantly induced by EGFRvIII overexpression, both in vitro and in vivo. Constitutive knockdown of Angptl4 in LN229-vIII using shRNA significantly decreased the microvessel density in the tumor xenografts and suppressed tumor growth. To clarify the regulatory mechanisms of Angptl4 by EGFRvIII, we analyzed the signaling pathways and transcription factors by pharmacological inhibition and RNA interference. U0126, an ERK signal inhibitor dramatically suppressed Angptl4 expression. The transcription factor c-Myc, which is regulated by ERK, was activated in the LN229-vIII cells and knockdown of c-Myc using siRNA also attenuated Angptl4 expression in the LN229-vIII cells. Furthermore, chromatin immunoprecipitation (ChIP) assay revealed increased recruitment of c-Myc to the promoter region of Angptl4 in the LN229-vIII cells. In summary, we demonstrated that EGFRvIII induces Angptl4 expression through the ERK/c-Myc pathway and promotes tumor angiogenesis in malignant gliomas.
登录
查看更多内容
影响因子：
8
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.
通讯作者：
Furnari, F. B.
影响因子：
20.1
作者：
Cazes, Aurelie;Galaup, Ariane;Monnot, Catherine
通讯作者：
Monnot, Catherine
DOI：
10.1073/pnas.0609025103
发表时间：
2006-12-05
影响因子：
11.1
作者：
Galaup, Ariane;Cazes, Aurelie;Germain, Stephane
通讯作者：
Germain, Stephane
影响因子：
15.9
作者：
Gao, Sizhi Paul;Mark, Kevin G.;Bromberg, Jacqueline F.
通讯作者：
Bromberg, Jacqueline F.
影响因子：
4.1
作者：
Kim, I;Kim, HG;Koh, GY
通讯作者：
Koh, GY