Wang YJ, Zhi ZZ, Liu T, Kang J, Xu GH. Long non-coding RNA GAS5 promotes neuronal apoptosis in spinal cord injury via the miR-21/PTEN axis. World J Orthop 2025; 16(5): 106183 [DOI: 10.5312/wjo.v16.i5.106183]
Corresponding Author of This Article
Jian Kang, MD, Department of Spine Surgery, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, China. kangjian_spine@126.com
Research Domain of This Article
Biochemistry & Molecular Biology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
World J Orthop. May 18, 2025; 16(5): 106183 Published online May 18, 2025. doi: 10.5312/wjo.v16.i5.106183
Long non-coding RNA GAS5 promotes neuronal apoptosis in spinal cord injury via the miR-21/PTEN axis
Ying-Jie Wang, Zhong-Zheng Zhi, Tao Liu, Jian Kang, Guang-Hui Xu
Ying-Jie Wang, Department of Spine Surgery, East Hospital Affiliated to Tongji University School of Medicine, Shanghai 200120, China
Zhong-Zheng Zhi, Tao Liu, Jian Kang, Department of Spine Surgery, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, China
Guang-Hui Xu, Shanghai General Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai Jiao Tong University, Shanghai 200032, China
Co-corresponding authors: Jian Kang and Guang-Hui Xu.
Author contributions: Kang J and Xu GH contributed equally to this study as co-corresponding authors; Wang YJ, Zhi ZZ, and Kang J participated in writing the manuscript; Wang YJ, Zhi ZZ, and Liu T performed the project administration and data collection; Wang YJ and Kang J performed the data curation, formal analysis, and validation; Kang J and Xu GH helped examine and correct the manuscript; All authors have read and approved the final manuscript.
Supported by the Major Research Plan from the Health Commission of Hongkou District, No. 2001-03; and Academic Subject Boosting Plan in the Shanghai Fourth People’s Hospital affiliated to Tongji University School of Medicine Shanghai, No. SY-XKZT-2020-1003.
Institutional animal care and use committee statement: Ethical approval was obtained from Animal Care and Use Committee of Tongji University School of Medicine (ID: WTPZ20230612001).
Conflict-of-interest statement: The authors have no conflicts of interest to declare.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Data sharing statement: Data and requests for materials should be addressed to Jian Kang.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Jian Kang, MD, Department of Spine Surgery, Shanghai Fourth People's Hospital Affiliated to Tongji University School of Medicine, Shanghai 200434, China. kangjian_spine@126.com
Received: February 19, 2025 Revised: March 18, 2025 Accepted: April 17, 2025 Published online: May 18, 2025 Processing time: 87 Days and 5.3 Hours
Abstract
BACKGROUND
Spinal cord injury (SCI) is a severe and permanent trauma that often leads to significant motor, sensory, and autonomic dysfunction. Neuronal apoptosis is a major pathomechanism underlying secondary injury in SCI. Long non-coding RNAs (lncRNAs) have emerged as key regulators of gene expression and cellular processes, including apoptosis. However, the role of lncRNA growth arrest-specific transcript 5 (GAS5) in SCI-induced neuronal apoptosis remains unclear.
AIM
To investigate the role of lncRNA GAS5 in SCI-induced neuronal apoptosis via its interaction with microRNA (miR)-21 and the phosphatase and tensin homolog (PTEN)/AKT pathway.
METHODS
SCI rat models and hypoxic neuronal cell models were established. Motor function was assessed using the Basso-Beattie-Bresnahan score. Expression levels of GAS5, miR-21, PTEN, caspase 3, B-cell lymphoma 2 (Bcl-2), Bcl-2-associated X protein (Bax), and AKT were measured using quantitative PCR or Western blot analysis. Neuronal apoptosis was determined by TUNEL staining. Dual-luciferase reporter assays validated GAS5-miR-21 binding. Knockdown and overexpression experiments explored the functional effects of the GAS5/miR-21 axis.
RESULTS
GAS5 was significantly upregulated in the spinal cord following SCI, coinciding with increased neuronal apoptosis and decreased AKT activation. In vitro experiments demonstrated that GAS5 acted as a molecular sponge for miR-21, leading to increased PTEN expression and inhibition of the AKT signaling pathway, thereby promoting apoptosis. In vivo, GAS5 knockdown attenuated neuronal apoptosis, enhanced AKT activation, and improved motor function recovery in SCI rats.
CONCLUSION
GAS5 promotes neuronal apoptosis in SCI by binding to miR-21 and upregulating PTEN expression, inhibiting the AKT pathway. Targeting GAS5 may represent a novel therapeutic strategy for SCI.
Core Tip: This study investigated the role of long non-coding RNA growth arrest-specific transcript 5 (GAS5) in spinal cord injury (SCI)-induced neuronal apoptosis. We demonstrate that GAS5 acts as a molecular sponge to bind miR-21, thereby upregulating phosphatase and tensin homolog (PTEN) expression and inhibiting the AKT signaling pathway, ultimately promoting neuronal apoptosis. Inhibiting GAS5 expression alleviates neuronal apoptosis and improves motor function recovery in SCI rat models, suggesting that targeting GAS5 may be a promising therapeutic strategy for SCI.
