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FHL2 interacts with EGFR to promote glioblastoma growth

Oncogenevolume 37pages13861398 (2018) | Download Citation


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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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.). We thank Drs. Yu Wei and Ju Chen for the generous gifts of FHL2 null MEF cells and FHL2 knockout newborn mice. M.L. was also partially supported by Jiangsu distinguished Medical Professorship award.

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Author notes

  1. Lili Sun and Shuye Yu contributed equally to this work.


  1. The Experimental Center, the Second Affiliated Hospital of Soochow University, Suzhou, China

    • Lili Sun
    • , Shuye Yu
    • , Hui Xu
    • , Yanwen Zheng
    • , Aidong Wang
    •  & Ming Li
  2. Department of Neurology, the Second Affiliated Hospital of Soochow University, Suzhou, China

    • Shuye Yu
  3. Department of Neurosurgery, the Second Affiliated Hospital of Soochow University, Suzhou, China

    • Hui Xu
    • , Qing Lan
    •  & Ming Li
  4. Stem Cells and Biotherapy Engineering Research Center of Henan, Xinxiang Medical University, Xinxiang, China

    • Juntang Lin
  5. Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, China

    • Meiyan Wu
    •  & Jide Wang
  6. Ludwig Institute for Cancer Research, University of California, San Diego, CA, USA

    • Frank Furnari
    •  & Webster Cavenee
  7. Department of Neurology, University of Virginia, Charlottesville, VA, USA

    • Benjamin Purow
    •  & Ming Li


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Correspondence to Ming Li.

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