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

• Published in: International journal of molecular sciences Vol. 25; no. 18; p. 10229
• Main Authors: Guo, Xiaoxiao, Zhou, Han, Liu, Yifang, Xu, Wei, Kanwore, Kouminin, Zhang, Lin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 23.09.2024; MDPI
• Subjects: Animals; Brain cancer; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Cell adhesion & migration; Cell growth; cell invasion; Cell Line, Tumor; cell migration; Cell Movement - genetics; Development and progression; Experiments; GDNF; Gene Expression Regulation, Neoplastic; Genes; Glial cell line-derived neurotrophic factor; Glial Cell Line-Derived Neurotrophic Factor - genetics; Glial Cell Line-Derived Neurotrophic Factor - metabolism; Glioblastoma - genetics; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma multiforme; glioblastomas; Glioma; Health aspects; Humans; Male; Mice; Mice, Nude; Neoplasm Invasiveness; Phosphorylation; Physiological aspects; Plasminogen Activator Inhibitor 1 - genetics; Plasminogen Activator Inhibitor 1 - metabolism; Protease inhibitors; Proteins; SERPINE1; Signal Transduction; Smad2 Protein - genetics; Smad2 Protein - metabolism; SMAD2/3; Smad3 Protein - genetics; Smad3 Protein - metabolism; Survival analysis; Thrombin; Tumors; Wound healing; China; cell migration; cell invasion; GDNF; glioblastomas; SERPINE1; SMAD2/3
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms251810229

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.