机构：[1]The Experimental Center, the Second Affiliated Hospital of Soochow University, Suzhou, China[2]Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, China[3]Department of Neurosurgery, the Second Affiliated Hospital of Soochow University, Suzhou, China[4]Stem Cells and Biotherapy Engineering Research Center of Henan, Xinxiang Medical University, Xinxiang, China[5]Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China[6]Ludwig Institute for Cancer Research, University of California, San Diego, CA, USA[7]Department of Neurology, University of Virginia, Charlottesville, VA, USA
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.
基金：
This work was supported by grants from the
National Natural Science Foundation of China (81572480 and
81172401, to M.L.) and the Second Affiliated Hospital of Soochow
University Youth pre-Research Fund (SDFEYQN1607, to L.S.).
第一作者机构：[1]The Experimental Center, the Second Affiliated Hospital of Soochow University, Suzhou, China
共同第一作者：
通讯作者：
通讯机构：[1]The Experimental Center, the Second Affiliated Hospital of Soochow University, Suzhou, China[3]Department of Neurosurgery, the Second Affiliated Hospital of Soochow University, Suzhou, China[7]Department of Neurology, University of Virginia, Charlottesville, VA, USA
推荐引用方式(GB/T 7714)：
Lili Sun,Shuye Yu,Hui Xu,et al.FHL2 interacts with EGFR to promote glioblastoma growth[J].ONCOGENE.2018,37(10):1386-1398.doi:10.1038/s41388-017-0068-0.
APA：
Lili Sun,Shuye Yu,Hui Xu,Yanwen Zheng,Juntang Lin...&Ming Li.(2018).FHL2 interacts with EGFR to promote glioblastoma growth.ONCOGENE,37,(10)
MLA：
Lili Sun,et al."FHL2 interacts with EGFR to promote glioblastoma growth".ONCOGENE 37..10(2018):1386-1398
医学