MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of osteosarcoma cells

Author:

Wang Jianshu1,Li Jing1,Xue Jinxu1,Ma Baijing2,Zhu Yanqi1,Tian Caiping2

Affiliation:

1. Gansu Provincial Cancer Hospital

2. Gansu Provincial Academic Institute for Medical Research

Abstract

Abstract

Objective To investigate the influence of MEK5/ERK5 pathway on mitophagy in osteosarcoma (OS), as well as the involved molecular mechanisms. Methods The overlapped genes of mitophagy-related genes from MSigDB database and DEGs between metastatic and primary OS groups from GSE32981 were identified. GSVA of mitophagy-related pathways between the metastatic and primary groups were analyzed. The relationships between Nur77 and mitophagy-related pathways, prognosis were investigated. Western blotting was utilized to assess protein levels of MEK5, ERK5, p-ERK5, Nur77, PINK1, and Parkin. Cellular behaviors and mitochondrial potential were evaluated via CCK-8, Transwell assay and JC-1 staining. Results Total 4 overlapped genes were obtained as mitophagy-related DEGs, including GABARAPL1, HIF1A, PINK1, RB1CC1. The activity scores of 3 mitophagy-related pathways exhibited significant differences between metastatic and primary groups. Importantly, Nur77 was significantly negatively correlated with a mitophagy-related pathway (GOBP MITOPHAGY: R = -0.48, P = 0.02). The Nur77 expression in metastatic group was remarkedly higher than that in the primary group (P < 0.001). Patients with high Nur77 expression had poor prognosis, with AUC values all above 0.615 in predicting 1, 3, and 5 years survival. In addition, MEK5/ERK5 pathway is activated in OS, and MEK5/ERK pathway promotes Nur77 expression, tumorigenesis and mitochondrial function in U2OS cells. Cytosporone B implement significantly increased the tumorigenesis of U2OS cells in sh-MEK5 group, and inhibited the weaken in mitochondrial membrane potential caused by MEK5 downregulation, and reversed the protein levels of mitophagy markers PINK1 and Parkin in sh-MEK5 group. Conclusion MEK5-ERK5 pathway mediates mitophagy by regulating Nur77 to promote tumorigenesis of OS cells. These findings offered promising therapeutic targets for OS.

Publisher

Springer Science and Business Media LLC

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3