中国神经再生研究(英文版) ›› 2022, Vol. 17 ›› Issue (8): 1776-1784.doi: 10.4103/1673-5374.332156

• 原著:脑损伤修复保护与再生 • 上一篇    下一篇

肺腺癌转移性相关转录本1:减轻创伤性脑损伤的“秘钥”

  

  • 出版日期:2022-08-15 发布日期:2022-01-22
  • 基金资助:
    国家自然科学基金项目(81571159);国家自然科学基金项目(青年项目)(81601072);重庆市自然科学基金项目(cstc2019jcyj-msxmX0830)

Essential role of MALAT1 in reducing traumatic brain injury

Na Wu1, #, Chong-Jie Cheng1, #, Jian-Jun Zhong1, Jun-Chi He1, Zhao-Si Zhang1, Zhi-Gang Wang1, Xiao-Chuan Sun1, Han Liu1, 2, *   

  1. 1Department of Neurosurgery, the First Affiliated Hospital of Chongqing Medical University, Chongqing, China; 2Department of Neurosurgery, Qilu Hospital of Shandong University (Qingdao Campus), Qingdao, Shandong Province, China
  • Online:2022-08-15 Published:2022-01-22
  • Contact: Han Liu, PhD, 1019266517@qq.com.
  • Supported by:
    The study was supported by the National Natural Science Foundation of China, No. 81571159 (to XCS); the National Natural Science Foundation of China (Youth Program), No. 81601072 (to CJC); and the Natural Science Foundation of Chongqing, China, No. cstc2019jcyj-msxmX0830 (to CJC).

摘要:

肺腺癌转移性相关转录本1作为一种高度进化的保守长链非编码RNA,已被证明可通过促进血管生成影响肺肿瘤的转移。为探索其在创伤性脑损伤中的作用,实验构建控制性皮质撞击小鼠模型和氧糖剥夺细胞模型以在体内外模拟创伤性脑损伤。结果发现,体外沉默肺腺癌转移性相关转录本1可抑制创伤性脑损伤小鼠内皮细胞活力和管形成,但增加了内皮细胞的迁移。同时肺腺癌转移性相关转录本1缺陷小鼠在创伤性脑损伤后表现出损伤皮质中内皮细胞的增殖、功能性血管密度以及脑血流量降低。进一步生物信息学分析以及体外RNA下拉实验分析证实EZH2是内皮细胞中肺腺癌转移性相关转录本1的下游元件。最后NOTCH1的激动剂Jagged1可逆转了肺腺癌转移性相关转录本1缺失介导的血管生成损伤。由此表明肺腺癌转移性相关转录本1以EZH2/NOTCH1依赖性方式调控创伤性脑损伤后血管生成。

https://orcid.org/0000-0001-5726-8751 (Han Liu); https://orcid.org/0000-0001-8806-2422 (Na Wu)

关键词: 创伤性脑损伤, 肺腺癌转移性相关转录本1, 血管生成, EZH2, NOTCH1, 长链非编码RNA, 控制性皮质撞击, 氧糖剥夺

Abstract: As a highly evolutionary conserved long non-coding RNA, metastasis associated lung adenocarcinoma transcript 1 (MALAT1) was first demonstrated to be related to lung tumor metastasis by promoting angiogenesis. To investigate the role of MALAT1 in traumatic brain injury, we established mouse models of controlled cortical impact and cell models of oxygen-glucose deprivation to mimic traumatic brain injury in vitro and in vivo. The results revealed that MALAT1 silencing in vitro inhibited endothelial cell viability and tube formation but increased migration. In MALAT1-deficient mice, endothelial cell proliferation in the injured cortex, functional vessel density and cerebral blood flow were reduced. Bioinformatic analyses and RNA pull-down assays validated enhancer of zeste homolog 2 (EZH2) as a downstream factor of MALAT1 in endothelial cells. Jagged-1, the Notch homolog 1 (NOTCH1) agonist, reversed the MALAT1 deficiency-mediated impairment of angiogenesis. Taken together, our results suggest that MALAT1 controls the key processes of angiogenesis following traumatic brain injury in an EZH2/NOTCH1-dependent manner.

Key words: angiogenesis, controlled cortical impact, EZH2, Jagged-1, LncRNA, MALAT1, NOTCH1, oxygen-glucose deprivation, traumatic brain injury, vascular remodeling