Oncotarget

Research Papers:

Transcriptional downregulation of microRNA-19a by ROS production and NF-κB deactivation governs resistance to oxidative stress-initiated apoptosis

Jun Hong, Ying Wang, Bang-Chuan Hu, Liang Xu, Jing-Quan Liu, Min-Hua Chen, Jin-Zhu Wang, Fang Han, Yang Zheng, Xu Chen, Qian Li, Xiang-Hong Yang, Ren-Hua Sun _ and Shi-Jing Mo

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Oncotarget. 2017; 8:70967-70981. https://doi.org/10.18632/oncotarget.20235

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Abstract

Jun Hong1,*, Ying Wang2,*, Bang-Chuan Hu1,*, Liang Xu1, Jing-Quan Liu1, Min-Hua Chen1, Jin-Zhu Wang1, Fang Han1, Yang Zheng1, Xu Chen1, Qian Li1, Xiang-Hong Yang1, Ren-Hua Sun1 and Shi-Jing Mo1

1Department of Critical Care Medicine, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310000, China

2Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai 200040, China

*These authors have contributed equally to this work

Correspondence to:

Ren-Hua Sun, email: [email protected]

Shi-Jing Mo, email: [email protected]

Keywords: microRNA-19a, ROS, NF-κB, oxidative stress, apoptosis

Received: June 21, 2017    Accepted: July 26, 2017    Published: August 12, 2017

ABSTRACT

Cell apoptosis is one of the main pathological alterations during oxidative stress (OS) injury. Previously, we corroborated that nuclear factor-κB (NF-κB) transactivation confers apoptosis resistance against OS in mammalian cells, yet the underlying mechanisms remain enigmatic. Here we report that microRNA-19a (miR-19a) transcriptionally regulated by reactive oxygen species (ROS) production and NF-κB deactivation prevents OS-initiated cell apoptosis through cylindromatosis (CYLD) repression. CYLD contributes to OS-initiated cell apoptosis, for which NF-κB deactivation is essential. MiR-19a directly represses CYLD via targeting 3′ UTR of CYLD, thereby antagonizing OS-initiated apoptosis. CYLD repression by miR-19a restores the IKKβ phosphorylation, RelA disassociation from IκBα, IκBα polyubiquitination and degradation, RelA recruitment at VEGF gene promoter as well as VEGF secretion in the context of OS. Either pharmacological deactivation of NF-κB or genetic upregulation of CYLD compromises the apoptosis-resistant phenotypes of miR-19a. Furthermore, miR-19a is transcriptionally downregulated upon OS in two distinct processes that require ROS production and NF-κB deactivation. VEGF potentiates the ability of miR-19a to activate NF-κB and render apoptosis resistance. Our findings underscore a putative mechanism whereby CYLD repression-mediated and NF-κB transactivation-dependent miR-19a regulatory feedback loop prevents cell apoptosis in response to OS microenvironment.


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