Guanylate binding protein-1 mediates EGFRvIII and promotes glioblastoma growth in vivo but not in vitro.
Guanylate binding protein-1 mediates EGFRvIII and promotes glioblastoma growth in vivo but not in vitro.
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鸟苷酸结合蛋白-1 在体内介导 EGFRvIII 并促进胶质母细胞瘤生长，但在体外则不然
DOI：
10.18632/oncotarget.7109
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发表时间：
2016-03-01
期刊：
影响因子：
--
通讯作者：
Li M
中科院分区：
文献类型：
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作者：
Lan Q;Wang A;Cheng Y;Mukasa A;Ma J;Hong L;Yu S;Sun L;Huang Q;Purow B;Li M
多形性胶质母细胞瘤（GBM）是成人中最常见和致命的原发性脑肿瘤。表皮生长因子受体（EGFR）在GBM中经常扩增和突变。我们之前报道过鸟苷酸结合蛋白1 （Guanylate binding protein-1, GBP1）是EGFR的一个新的转录靶基因，在GBM侵袭中起作用。在这里，我们证明了EGFRvIII也可以通过p38 MAPK/阴阳1 （YY1）信号通路在转录水平诱导GBP1。在体外和小鼠模型中，通过RNA干扰沉默GBP1可显著抑制egfrviii介导的GBM细胞增殖。过表达GBP1对胶质母细胞瘤细胞体外增殖无明显影响。相反，在原位胶质瘤小鼠模型中，GBP1过表达通过增加肿瘤细胞增殖和减少肿瘤细胞凋亡，显著促进胶质瘤的生长，降低胶质瘤小鼠的存活率。在临床上，GBP1在人GBM肿瘤中表达升高，与GBM标本中EGFRvIII的状态呈正相关，其表达与GBM患者的生存率呈负相关。综上所述，这些结果表明GBP1可能是EGFRvIII突变GBMs的潜在治疗靶点。
Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults. Epidermal growth factor receptor (EGFR) is frequently amplified and mutated in GBM. We previously reported that Guanylate binding protein-1 (GBP1) is a novel transcriptional target gene of EGFR and plays a role in GBM invasion. Here we demonstrate that GBP1 can also be induced by EGFRvIII at the transcriptional level through the p38 MAPK/Yin Yang 1 (YY1) signaling pathway. Silencing of GBP1 by RNA interference significantly inhibits EGFRvIII-mediated GBM cell proliferation in vitro and in a mouse model. Overexpression of GBP1 has no obvious effect on glioblastoma cell proliferation in vitro. In contrast, in an orthotopic glioma mouse model GBP1 overexpression significantly promotes glioma growth and reduces survival rate of glioma-bearing mice by increasing cell proliferation and decreasing cell apoptosis in tumor. Clinically, GBP1 expression is elevated in human GBM tumors and positively correlates with EGFRvIII status in GBM specimens, and its expression is inversely correlated with the survival rate of GBM patients. Taken together, these results reveal that GBP1 may serve as a potential therapeutic target for GBMs with EGFRvIII mutation.