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

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. 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. 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. 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.

Citation

Yuduo Guo, Xin He, Mingshan Zhang, Yanming Qu, Chunyu Gu, Ming Ren, Haoran Wang, Weihai Ning, Junfa Li, Chunjiang Yu, Hongwei Zhang. Reciprocal control of ADAM17/EGFR/Akt signaling and miR-145 drives GBM invasiveness. Journal of neuro-oncology. 2020 Apr;147(2):327-337

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PMID: 32170633

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