The Experimental Center, the Second Affiliated Hospital of Soochow University, Suzhou, China.
Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, China.
Oncogene. 2018 Mar;37(10):1386-1398. doi: 10.1038/s41388-017-0068-0. Epub 2018 Jan 11.
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.
四半 LIM 蛋白 2（FHL2）是 LIM 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 在神经胶质瘤（GBM）中上调并发挥致癌作用，GBM 是最常见和侵袭性最强的脑肿瘤。GBM 还具有表皮生长因子受体（EGFR）基因的扩增及其突变，其中 EGFRvIII 是最常见且功能最重要的。在这里，我们报告 FHL2 与 GBM 细胞中的野生型 EGFR 和其突变的 EGFRvIII 形式物理相互作用。FHL2 的表达导致 EGFR 和 EGFRvIII 蛋白水平升高，这是由于蛋白稳定性增加而不是 EGFR mRNA 表达增加所致。相比之下，使用 RNA 干扰进行 FHL2 敲低会降低 EGFR 和 EGFRvIII 蛋白表达以及 EGFR 和 AKT 的磷酸化水平。与这些特征一致，在缺乏 FHL2 的小鼠星形胶质细胞中，EGFR 表达明显降低，在这些细胞中重新引入 FHL2 能够恢复 EGFR 水平。使用已建立的 GBM 细胞系和患者来源的神经球系，FHL2 沉默显著诱导 EGFRvIII 阳性细胞中的细胞凋亡。在体内，靶向 FHL2 显著阻止了 EGFRvIII 阳性 GBM 肿瘤的生长。FHL2 表达也与患者 GBM 样本中的 EGFR 表达呈正相关。总之，我们的结果表明，FHL2 与 EGFR 和 EGFRvIII 相互作用以增加其水平，从而促进神经胶质瘤的生长，代表了一种可能具有治疗靶向性的新机制。
