Research Papers:

microRNA-25 targets PKCζ and protects osteoblastic cells from dexamethasone via activating AMPK signaling

Jian-bo Fan _, Wei Liu, Xin-hui Zhu, Hong Yi, Sheng-yu Cui, Jian-ning Zhao and Zhi-ming Cui

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Oncotarget. 2017; 8:3226-3236. https://doi.org/10.18632/oncotarget.13698

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Jian-bo Fan1,2,*, Wei Liu1,*, Xin-hui Zhu1, Hong Yi1, Sheng-yu Cui1, Jian-ning Zhao2, Zhi-ming Cui1

1Department of Orthopaedics, The Second Affiliated Hospital of Nantong University, Nantong 226001, Jiangsu, PR China

2Department of Orthopaedics, Jinling Hospital, Nanjing Medical University, Nanjing 210008, Jiangsu, PR China

*These authors have contributed equally to this work

Correspondence to:

Zhi-ming Cui, email: [email protected]

Keywords: dexamethasone, osteoblastic cells, microRNA-25, PKCζ, AMP-activated protein kinase (AMPK)

Received: July 27, 2016    Accepted: November 14, 2016    Published: November 29, 2016


AMP-activated protein kinase (AMPK) activation could protect osteoblasts from dexamethasone (Dex). This study aims to provoke AMPK activation via microRNA downregulation of its negative regulator protein kinase C ζ (PKCζ). Results show that microRNA-25-5p (miR-25-5p) targets PKCζ’s 3’ untranslated regions (UTRs). Forced-expression of miR-25 downregulated PKCζ and activated AMPK in human osteoblastic cells (OB-6 and hFOB1.19 lines), which thereafter protected cells from Dex. Reversely, expression of antagomiR-25, the miR-25 inhibitor, upregulated PKCζ and inhibited AMPK activation, exacerbating Dex damages. Notably, PKCζ shRNA knockdown similarly activated AMPK and protected osteoblastic cells from Dex. AMPK activation was required for miR-25-induced osteoblastic cell protection. AMPKα shRNA or dominant negative mutation almost completely blocked miR-25-induced cytoprotection against Dex. Further studies showed that miR-25 expression increased NADPH activity and suppressed Dex-induced oxidative stress in osteoblastic cells. Such effects by miR-25 were abolished with AMPKα knockdown or mutation. Significantly, miR-25-5p level was increased in patients’ necrotic femoral head tissues, which was correlated with PKCζ downregulation and AMPK hyper-activation. These results suggest that miR-25-5p targets PKCζ and protects osteoblastic cells from Dex possibly via activating AMPK signaling.

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