Dysregulation of cPWWP2A-miR-579 axis mediates dexamethasone-induced cytotoxicity in human osteoblasts
Dysregulation of cPWWP2A-miR-579 axis mediates dexamethasone-induced cytotoxicity in human osteoblasts
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DOI：
10.1016/j.bbrc.2019.07.095
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发表时间：
2019-09-24
影响因子：
3.1
通讯作者：
Cui, Zhiming
中科院分区：
文献类型：
--
作者：
Hong, Hongxiang;Sun, Yuyu;Cui, Zhiming
地塞米松（DEX）对人成骨细胞具有明显的细胞毒性。cPWWP 2A是最近发现的新型环状RNA（circRNA），作为microRNA-579（miR-579）的内源性海绵。本研究测试了cPWWP 2A-miR-579轴在DEX处理的成骨细胞中的表达和潜在功能。我们发现，cPWWP 2A在DEX服用的人类患者的坏死股骨头组织中以及在DEX治疗的人类成骨细胞中下调。在06-6成骨细胞和原代人成骨细胞中，cPWWP 2A的异位过表达有效地抑制了DEX诱导的miR-579积累、细胞死亡、凋亡和程序性坏死。通过靶向siR-NAs沉默miR-579也减弱了人成骨细胞中DEX诱导的细胞毒性。值得注意的是，模拟DEX诱导的作用，cPWWP 2A沉默或强制miR-579过表达在人成骨细胞中诱导了显著的细胞毒性。进一步的分析表明，miR-579的靶点，包括SIRT 1和PDK 1（磷酸肌醇依赖性蛋白激酶1），在DEX处理的成骨细胞中下调。在服用DEX的人类患者的坏死股骨头组织中，它们的水平也降低了。综上所述，我们表明cPWWP 2A-miR-579轴的失调参与了人成骨细胞中DEX诱导的细胞毒性。(C)2019爱思唯尔公司All rights reserved.
Dexamethasone (DEX) induces significant cytotoxicity to human osteoblasts. cPWWP2A is recently-indentifled novel circular RNA (circRNA), acting as an endogenous sponge of microRNA-579 (miR-579). The present study tested the expression and potential functions of the cPWWP2A-miR-579 axis in DEX-treated osteoblasts. We show that cPWWP2A is downregulated in the necrotic femoral head tissues of DEX-taking human patients as well as in DEX-treated human osteoblasts. In 06-6 osteoblastic cells and primary human osteoblasts ectopic overexpression of cPWWP2A potently inhibited DEX-induced miR-579 accumulation, cell death, apoptosis and programmed necrosis. Silencing miR-579, by targeted siR-NAs, also attenuated DEX-induced cytotoxicity in human osteoblasts. Significantly, mimicking DEX-induced actions, cPWWP2A silencing or forced miR-579 overexpression induced significant cytotoxicity in human osteoblasts. Further analyses demonstrated that miR-579's targets, including SIRT1 and PDK1 (phosphoinositide-dependent protein kinase 1), were downregulated in DEX-treated osteoblasts. Their levels were decreased as well in the necrotic femoral head tissues of DEX-taking human patients. Taken together we show that dysregulation of the cPWWP2A-miR-579 axis is involved in DEX-induced cytotoxicity in human osteoblasts. (C) 2019 Elsevier Inc. All rights reserved.