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Reciprocal control of ADAM17/EGFR/Akt signaling and miR-145 drives GBM invasiveness

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Abstract

Introduction

Glioblastoma multiforme (GBM) is one of the most devastating brain malignancies worldwide and is considered to be incurable. However, the mechanisms underlying its aggressiveness remain unclear.

Methods

The expression of ADAM17 in tissue samples was detected by immunohistochemistry. Knockdown and rescue experiments were used to demonstrate the regulatory effect of ADAM17 on the invasion ability of GBM cells. Western Blot and qPCR were used to detect the expression of related proteins and RNAs. Moreover, a luciferase reporter assay was performed to verify whether miR-145 directly binds to the 3′-UTR of ADAM17.

Results

We revealed that ADAM17 was overexpressed in GBM tissues and correlated positively with poor prognosis. The knockdown of ADAM17 obviously suppressed the invasiveness of GBM cell lines. Furthermore, we found that knockdown of ADAM17 decreased activation of EGFR/Akt/C/EBP-β signaling, and consequently upregulated miR-145 expression in GBM cell lines. Notably, miR-145 directly targeted the ADAM17 3′-UTR and suppressed expression levels of ADAM17.

Conclusions

Our findings define an ADAM17/EGFR/miR-145 feedback loop that drives the GBM invasion. Reciprocal regulation between ADAM17 and miR-145 results in aberrant activation of EGFR signaling, suggesting that inhibition of ADAM17 expression can be an ideal therapeutic strategy for the treatment of GBM.

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Acknowledgements

This study was supported by the Beijing Natural Science Foundation Program and Scientific Research Key Program of Beijing Municipal Commission of Education (No. KZ201510025030).

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Authors and Affiliations

  1. Department of Neurosurgery, Sanbo Brain Hospital, Capital Medical University, Beijing, 100093, People’s Republic of China

    Yuduo Guo, Xin He, Mingshan Zhang, Yanming Qu, Chunyu Gu, Ming Ren, Haoran Wang, Weihai Ning, Chunjiang Yu & Hongwei Zhang

  2. Department of Neurosurgery, The Third Medical Center of the General Hospital of the People’s Liberation Army, Beijing, 100039, People’s Republic of China

    Xin He

  3. Department of Neurobiology and Center of Stroke, Beijing Institute for Brain Disorders, Capital Medical University, Beijing, 100069, People’s Republic of China

    Junfa Li

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  1. Yuduo Guo
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Contributions

Conception and design: Yuduo Guo, Xin He, Junfa Li, Chunjiang Yu, Hongwei Zhang. Development of methodology: Yuduo Guo, Xin He, Junfa Li, Chunjiang Yu, Hongwei Zhang. Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): Yuduo Guo, Xin He, Junfa Li, Chunjiang Yu, Hongwei Zhang. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): Yuduo Guo, Xin He, Junfa Li, Chunjiang Yu, Hongwei Zhang. Writing, review, and/or revision of the manuscript: Yuduo Guo, Junfa Li, Chunjiang Yu, Hongwei Zhang. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): Yuduo Guo, Xin He, Mingshan Zhang, Yanming Qu, Chunyu Gu, Ming Ren, Haoran Wang, Weihai Ning Study supervision: Junfa Li, Chunjiang Yu, Hongwei Zhang.

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Correspondence to Hongwei Zhang.

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Guo, Y., He, X., Zhang, M. et al. Reciprocal control of ADAM17/EGFR/Akt signaling and miR-145 drives GBM invasiveness. J Neurooncol 147, 327–337 (2020). https://doi.org/10.1007/s11060-020-03453-4

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  • DOI: https://doi.org/10.1007/s11060-020-03453-4

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