Let-7f Regulates the Hypoxic Response in Cerebral Ischemia by Targeting NDRG3.
microRNAs are a class of non-coding RNAs including approximately 22 nucleotides in length and play a pivotal role in post-transcriptional gene regulation. Currently, the role of miRNAs in the pathophysiology of ischemic stroke has been the subject of recent investigations. In particular, antagomirs to microRNA (miRNA) let-7f have been found to be neuroprotective in vivo, although the detailed function of let-7f during cerebral ischemia has not been fully illustrated. NDRG3 is an N-myc downstream-regulated gene (NDRG) family member that has been observed in the nuclei in most brain cells. Recently, a NDRG3-mediated lactate signaling, in which stabilized NDRG3 protein can promote angiogenesis and cell growth by activating the Raf-ERK pathway in hypoxia was discovered. In this study, we preliminarily explored the change in the expression of the NDRG3 protein which indicated that NDRG3 protein is an oxygen-regulated protein in neurons in rat cerebral ischemia in vivo and in vitro. We further identified let-7f as an upstream regulator of NDRG3 by the lentiviral transfection of rat cortical neurons and the dual luciferase analysis of human genes. In addition, a dual-color fluorescence in situ hybridization assay showed that when the expression of let-7f was elevated, the expression of NDRG3 mRNA was accordingly reduced in rat cerebral ischemia. Taken together, our results identify a new regulatory mechanism of let-7f on NDRG3 expression in the hypoxic response of cerebral ischemia and raise the possibility that the let-7f/NDRG3 pathway may serve as a potential target for the treatment of ischemic stroke.
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Yaobing
Y
Yao
Department of Pathology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.|Department of Pathology, The College of Basic Medicine of Zhengzhou University, Zhengzhou, 450052, China.
Weiwei
W
Wang
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.
Lijun
L
Jing
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Yiwen
Y
Wang
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Mingzhe
M
Li
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Xiaocan
X
Hou
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.|Institute of Clinical Medicine, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
Jing
J
Wang
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.
Tao
T
Peng
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China.
Junfang
J
Teng
Department of Neurology, The First Affiliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Zhengzhou, 450052, China. jiayanjie1971@zzu.edu.cn.
Yanjie
Y
Jia
D000818:Animals; D000831:Animals, Newborn; D002545:Brain Ischemia / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000502:physiology; D018390:Gene Targeting / Q000379:methods; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis* / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000096:biosynthesis* / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley
D047908:Intracellular Signaling Peptides and Proteins; D035683:MicroRNAs; C431706:NDRG3 protein, human; D009419:Nerve Tissue Proteins; C487931:mirnlet7 microRNA, human
Cerebral ischemia; Hypoxic response; Let-7f; N-myc downstream-regulated gene-3 (NDRG3); microRNAs (miRNAs)