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microRNA-135b expression silences Ppm1e to provoke AMPK activation and inhibit osteoblastoma cell proliferation

2017; Impact Journals LLC; Volume: 8; Issue: 16 Linguagem: Inglês

10.18632/oncotarget.15477

1949-2553

Zhengwei Li, Yun-Rong Zhu, Xiaozhong Zhou, Baobiao Zhuo, Xiaodong Wang,

Cancer, Hypoxia, and Metabolism

// Zheng-Wei Li 1, * , Yun-Rong Zhu 2, * , Xiao-Zhong Zhou 3, 4, * , Bao-Biao Zhuo 1 , Xiao-Dong Wang 1 1 The Center of Diagnosis and Treatment for Children's Bone Diseases, The Children's Hospital Affiliated to Soochow University, Suzhou, China 2 Department of Orthopedics, The Affiliated Jiangyin Hospital of Medical College of Southeast University, Jiangyin City, China 3 Department of Orthopedics, The Second Affiliated Hospital of Soochow University, Suzhou, China 4 Department of Orthopedics, The First People's Hospital of SuQian, SuQian, China * Co-first authors Correspondence to: Xiao-Dong Wang, email: xiaodongwangsz@163.com Keywords: microRNA-135b, Ppm1e, AMPK, osteoblastoma, cell proliferation Received: January 20, 2017 Accepted: February 08, 2017 Published: February 18, 2017 ABSTRACT Forced-activation of AMP-activated protein kinase (AMPK) can possibly inhibit osteoblastoma cells. Here, we aim to provoke AMPK activation via microRNA silencing its phosphatase Ppm1e (protein phosphatase Mg 2+ /Mn 2+ -dependent 1e). We showed that microRNA-135b-5p ("miR-135b-5p"), the anti-Ppm1e microRNA, was significantly downregulated in human osteoblastoma tissues. It was correlated with Ppm1e upregulation and AMPKα1 de-phosphorylation. Forced-expression of miR-135b-5p in human osteoblastoma cells (MG-63 and U2OS lines) silenced Ppm1e, and induced a profound AMPKα1 phosphorylation (at Thr-172). Osteoblastoma cell proliferation was inhibited after miR-135b-5p expression. Intriguingly, Ppm1e shRNA knockdown similarly induced AMPKα1 phosphorylation, causing osteoblastoma cell proliferation. Reversely, AMPKα1 shRNA knockdown or dominant negative mutation almost abolished miR-135b-5p's actions in osteoblastoma cells. Further in vivo studies demonstrated that U2OS tumor growth in mice was dramatically inhibited after expressing miR-135b-5p or Ppm1e shRNA. Together, our results suggest that miR-135b-induced Ppm1e silence induces AMPK activation to inhibit osteoblastoma cell proliferation.