microRNA-455 targets cullin 3 to activate Nrf2 signaling and protect human osteoblasts from hydrogen peroxide

Dawei Xu; Hao Zhu; Chengniu Wang; Xinhui Zhu; Genxiang Liu; Chu Chen; Zhiming Cui

doi:10.18632/oncotarget.19486

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Research Papers:

microRNA-455 targets cullin 3 to activate Nrf2 signaling and protect human osteoblasts from hydrogen peroxide

Dawei Xu, Hao Zhu, Chengniu Wang, Xinhui Zhu, Genxiang Liu, Chu Chen and Zhiming Cui _

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Oncotarget. 2017; 8:59225-59234. https://doi.org/10.18632/oncotarget.19486

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Abstract

Dawei Xu1,*, Hao Zhu2,*, Chengniu Wang3, Xinhui Zhu1, Genxiang Liu2, Chu Chen1 and Zhiming Cui1

1Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong, China

2Department of Orthopaedics, The Fourth Affiliated Hospital of Nantong University, Yancheng, China

3Basic Medical Research Centre, Medical College, Nantong University, Nantong, China

*These author have contributed equally to this work

Correspondence to:

Zhiming Cui, email: [email protected]

Keywords: osteoblast, hydrogen peroxide (H₂O₂), Nrf2, microRNA-455, cullin 3 (Cul3)

Received: May 05, 2017 Accepted: June 19, 2017 Published: July 22, 2017

ABSTRACT

Over-production of hydrogen peroxide (H₂O₂) will lead to human osteoblast dysfunction and apoptosis, causing progression of osteoporosis and osteonecrosis. NF-E2-related factor 2 (Nrf2) is a well-characterized anti-oxidant signaling. Cullin 3 (Cul3) ubiquitin E3 ligase dictates Nrf2 degradation. We demonstrate that microRNA-455 (“miR-455”) is a putative Cul3-targeting microRNA. Forced-expression of miR-455 in both hFOB1. 19 osteoblast cell line and primary human osteoblasts induced Cul3 degradation and Nrf2 protein stabilization, which led to subsequent transcription of ARE (anti-oxidant response element)-dependent genes (NQO1, HO1 and GCLC). Cul3 silencing, by expressing miR-455 or targeted-shRNA, protected human osteoblasts from H₂O₂. Reversely, miR-455 anti-sense caused Cul3 accumulation and Nrf2 degradation, which exacerbated H₂O₂ damages in hFOB1. 19 cells. Moreover, forced over-expression of Cul3 in hFOB1. 19 cells silenced Nrf2 and sensitized H₂O₂. Together, we propose that miR-455 activated Nrf2 signaling and protected human osteoblasts from oxidative stress possibly via targeting Cul3.

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Research Papers:

microRNA-455 targets cullin 3 to activate Nrf2 signaling and protect human osteoblasts from hydrogen peroxide

Abstract