Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma.
Guanylate binding protein 1 is a novel effector of EGFR-driven invasion in glioblastoma.
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DOI：
10.1084/jem.20111102
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发表时间：
2011-12-19
期刊：
影响因子：
--
通讯作者：
Furnari F
中科院分区：
文献类型：
--
作者：
Li M;Mukasa A;Inda MM;Zhang J;Chin L;Cavenee W;Furnari F
在多形性胶质母细胞瘤中，EGFR-GBP 1-基质金属蛋白酶-1级联驱动肿瘤侵袭，但不改变肿瘤增殖、存活或血管生成。虽然GBP 1（鸟苷酸结合蛋白1）是最早被鉴定的干扰素诱导蛋白之一，但其功能在很大程度上仍然未知。表皮生长因子受体（EGFR）的扩增或突变激活是多种人类肿瘤中最常见的遗传病变之一。这些包括多形性胶质母细胞瘤（GBM），其特征在于独立但相互关联的特征，即广泛侵入正常脑实质、快速生长、坏死和血管生成。在这项研究中，我们表明，EGFR激活促进GBM细胞系通过Src和p38丝裂原活化蛋白激酶的信号通路，促进GBP 1的表达。此外，我们确定YY 1（阴阳1）作为下游转录调节因子调节EGFR驱动的GBP 1表达。GBP 1是EGFR介导的MMP 1（基质金属蛋白酶1）表达和胶质瘤细胞体外侵袭所必需的。虽然GBP 1表达失调不影响胶质瘤细胞增殖，但过表达GBP 1通过MMP 1诱导增强胶质瘤细胞侵袭，这需要其C-末端螺旋结构域，并且不依赖于其GT3活性。通过RNA干扰降低侵袭性GBM细胞中的GBP 1水平也显著抑制了它们浸润小鼠脑实质的能力。在人GBM肿瘤和细胞系中，特别是神经亚型中，GBP 1的表达较高，并且与EGFR的表达呈正相关。总之，这些发现确立了GBP 1作为EGFR活性和MMP 1表达之间的先前未知的联系，并将其提名为抑制GBM侵袭的新的潜在治疗靶点。
In glioblastoma multiforme, an EGFR–GBP1–matrix metalloproteinase-1 cascade drives tumor invasion but does not alter tumor proliferation, survival, or angiogenesis. Although GBP1 (guanylate binding protein 1) was among the first interferon-inducible proteins identified, its function is still largely unknown. Epidermal growth factor receptor (EGFR) activation by amplification or mutation is one of the most frequent genetic lesions in a variety of human tumors. These include glioblastoma multiforme (GBM), which is characterized by independent but interrelated features of extensive invasion into normal brain parenchyma, rapid growth, necrosis, and angiogenesis. In this study, we show that EGFR activation promoted GBP1 expression in GBM cell lines through a signaling pathway involving Src and p38 mitogen-activated protein kinase. Moreover, we identified YY1 (Yin Yang 1) as the downstream transcriptional regulator regulating EGFR-driven GBP1 expression. GBP1 was required for EGFR-mediated MMP1 (matrix metalloproteinase 1) expression and glioma cell invasion in vitro. Although deregulation of GBP1 expression did not affect glioma cell proliferation, overexpression of GBP1 enhanced glioma cell invasion through MMP1 induction, which required its C-terminal helical domain and was independent of its GTPase activity. Reducing GBP1 levels by RNA interference in invasive GBM cells also markedly inhibited their ability to infiltrate the brain parenchyma of mice. GBP1 expression was high and positively correlated with EGFR expression in human GBM tumors and cell lines, particularly those of the neural subtype. Together, these findings establish GBP1 as a previously unknown link between EGFR activity and MMP1 expression and nominate it as a novel potential therapeutic target for inhibiting GBM invasion.
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影响因子：
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通讯作者：
Thomson, Elizabeth
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影响因子：
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作者：
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通讯作者：
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