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

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Abstract

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. AMPKa 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 AMPKa 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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Fan, J. B., Liu, W., Zhu, X. H., Yi, H., Cui, S. Y., Zhao, J. N., & Cui, Z. M. (2017). MicroRNA-25 targets PKCζ and protects osteoblastic cells from dexamethasone via activating AMPK signaling. Oncotarget, 8(2), 3226–3236. https://doi.org/10.18632/oncotarget.13698

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