FHL2 interacts with EGFR to promote glioblastoma growth.
FHL2 interacts with EGFR to promote glioblastoma growth.
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FHL2与EGFR相互作用促进胶质母细胞瘤生长
DOI：
10.1038/s41388-017-0068-0
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发表时间：
2018-03
期刊：
影响因子：
8
通讯作者：
Li M
中科院分区：
文献类型：
--
作者：
Sun L;Yu S;Xu H;Zheng Y;Lin J;Wu M;Wang J;Wang A;Lan Q;Furnari F;Cavenee W;Purow B;Li M
4 -半LIM蛋白2 （FHL2）是LIM-only蛋白家族的成员，在肿瘤发生中起着关键作用。我们之前报道过FHL2在胶质母细胞瘤（GBM）中上调并起致瘤作用，胶质母细胞瘤是最常见和侵袭性的脑肿瘤。GBM还以表皮生长因子受体（EGFR）基因的扩增及其突变为特征，其中EGFRvIII最为常见，在功能上也最为显著。在这里，我们报告了在GBM细胞中，FHL2与野生型EGFR及其突变的EGFRvIII形式发生物理相互作用。FHL2的表达导致EGFR和EGFRvIII蛋白水平升高，这是由于蛋白稳定性的增加，而不是由于EGFR mRNA表达的增加。相比之下，使用RNA干扰的FHL2敲除降低了EGFR和EGFRvIII蛋白的表达以及EGFR和AKT的磷酸化水平。与这些特征一致，EGFR表达在小鼠FHL2缺失的星形胶质细胞中显著降低，其中重新引入FHL2能够恢复EGFR水平。在已建立的GBM细胞系和患者来源的神经球细胞系中，FHL2沉默显著诱导egfrviii阳性细胞凋亡。靶向FHL2可显著阻止egfrviii阳性GBM肿瘤的体内生长。患者GBM样本中FHL2表达与EGFR表达也呈正相关。综上所述，我们的研究结果表明，FHL2与EGFR和EGFRvIII相互作用，提高其水平，从而促进胶质瘤的生长，这代表了一种可能具有治疗靶向性的新机制。
Four-and-a-half LIM protein2 (FHL2) is a member of the LIM-only protein family, which plays a critical role in tumorigenesis. We previously reported that FHL2 is upregulated and plays an oncogenic role in glioblastoma (GBM), the most common and aggressive brain tumor. GBM is also marked by amplification of the epidermal growth factor receptor (EGFR) gene and its mutations, of which EGFRvIII is the most common and functionally significant. Here we report that FHL2 physically interacts with the wild-type EGFR and its mutated EGFRvIII form in GBM cells. Expression of FHL2 caused increased EGFR and EGFRvIII protein levels and this was due to an increase in protein stability rather than an increase in EGFR mRNA expression. In contrast, FHL2 knockdown using RNA interference reduced EGFR and EGFRvIII protein expression and the phosphorylation levels of EGFR and AKT. Consistent with these features, EGFR expression was significantly lower in mouse FHL2-null astrocytes, where reintroduction of FHL2 was able to restore EGFR levels. Using established GBM cell lines and patient-derived neurosphere lines, FHL2 silencing markedly induced cell apoptosis in EGFRvIII-positive cells. Targeting FHL2 significantly prevented EGFRvIII-positive GBM tumor growth in vivo. FHL2 expression also positively correlated with EGFR expression in GBM samples from patients. Taken together, our results demonstrate that FHL2 interacts with EGFR and EGFRvIII to increase their levels and this promotes glioma growth, representing a novel mechanism that may be therapeutically targetable.
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影响因子：
8
作者：
Davies, G. C.;Ryan, P. E.;Lipkowitz, S.
通讯作者：
Lipkowitz, S.
影响因子：
21.3
作者：
Lin, SY;Makino, K;Hung, MC
通讯作者：
Hung, MC
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
影响因子：
--
作者：
Lan Q;Wang A;Cheng Y;Mukasa A;Ma J;Hong L;Yu S;Sun L;Huang Q;Purow B;Li M
通讯作者：
Li M
影响因子：
11.5
作者：
Fomchenko, Elena I.;Holland, Eric C.
通讯作者：
Holland, Eric C.
影响因子：
4.7
作者：
Purow, Benjamin W.;Sundaresan, Tilak K.;Fine, Howard A.
通讯作者：
Fine, Howard A.