胶质细胞源性神经营养因子通过 SMAD2/3-丝氨酸蛋白酶抑制剂 E1-信号轴促进胶质母细胞瘤细胞迁移和侵袭。

Glial-Cell-Line-Derived Neurotrophic Factor Promotes Glioblastoma Cell Migration and Invasion via the SMAD2/3-SERPINE1-Signaling Axis.

机构信息

Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang 222000, China.

Xuzhou Key Laboratory of Neurobiology, Department of Neurobiology and Anatomy, Xuzhou Medical University, Xuzhou 221004, China.

出版信息

Int J Mol Sci. 2024 Sep 23;25(18):10229. doi: 10.3390/ijms251810229.

DOI:10.3390/ijms251810229

PMID:39337713

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11432670/

Abstract

Glial-cell-line-derived neurotrophic factor (GDNF) is highly expressed and is involved in the malignant phenotype in glioblastomas (GBMs). However, uncovering its underlying mechanism for promoting GBM progression is still a challenging work. In this study, we found that serine protease inhibitor family E member 1 (SERPINE1) was a potential downstream gene of GDNF. Further experiments confirmed that SERPINE1 was highly expressed in GBM tissues and cells, and its levels of expression and secretion were enhanced by exogenous GDNF. SERPINE1 knockdown inhibited the migration and invasion of GBM cells promoted by GDNF. Mechanistically, GDNF increased SERPINE1 by promoting the phosphorylation of SMAD2/3. In vivo experiments demonstrated that GDNF facilitated GBM growth and the expressions of proteins related to migration and invasion via SERPINE1. Collectively, our findings revealed that GDNF upregulated SERPINE1 via the SMAD2/3-signaling pathway, thereby accelerating GBM cell migration and invasion. The present work presents a new mechanism of GDNF, supporting GBM development.

摘要

胶质细胞源性神经营养因子（GDNF）表达水平较高，并参与胶质母细胞瘤（GBM）的恶性表型。然而，揭示其促进 GBM 进展的潜在机制仍然是一项具有挑战性的工作。在这项研究中，我们发现丝氨酸蛋白酶抑制剂家族 E 成员 1（SERPINE1）是 GDNF 的一个潜在下游基因。进一步的实验证实，SERPINE1 在 GBM 组织和细胞中高度表达，其表达和分泌水平可被外源性 GDNF 增强。SERPINE1 敲低抑制了 GDNF 促进的 GBM 细胞的迁移和侵袭。在机制上，GDNF 通过促进 SMAD2/3 的磷酸化来增加 SERPINE1。体内实验表明，GDNF 通过 SERPINE1 促进 GBM 生长以及与迁移和侵袭相关的蛋白表达。总之，我们的研究结果揭示了 GDNF 通过 SMAD2/3 信号通路上调 SERPINE1，从而加速 GBM 细胞的迁移和侵袭。本研究为 GDNF 支持 GBM 发展提供了一个新的机制。