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.

中文翻译：

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ADAM17 / EGFR / Akt信号和miR-145的相互控制驱动了GBM的侵袭性。

摘要

介绍

多形胶质母细胞瘤（GBM）是全球最具破坏性的脑恶性肿瘤之一，被认为是无法治愈的。但是，其侵略性的潜在机制仍不清楚。

方法

通过免疫组织化学检测ADAM17在组织样品中的表达。敲低和抢救实验被用来证明ADAM17对GBM细胞侵袭能力的调节作用。Western Blot和qPCR用于检测相关蛋白和RNA的表达。此外，进行荧光素酶报告基因测定以验证miR-145是否直接结合ADAM17的3'-UTR。

结果

我们发现ADAM17在GBM组织中过表达，并且与不良预后呈正相关。抑制ADAM17明显抑制了GBM细胞系的侵袭性。此外，我们发现敲除ADAM17降低了EGFR / Akt / C /EBP-β信号传导的激活，并因此上调了GBM细胞系中的miR-145表达。值得注意的是，miR-145直接靶向ADAM17 3'-UTR，并抑制了ADAM17的表达水平。

结论

我们的发现定义了驱动GBM入侵的ADAM17 / EGFR / miR-145反馈回路。ADAM17和miR-145之间的相互调节会导致EGFR信号转导异常激活，这表明抑制ADAM17表达可能是治疗GBM的理想治疗策略。