Let-7f Regulates the Hypoxic Response in Cerebral Ischemia by Targeting NDRG3

• Published in: Neurochemical research Vol. 42; no. 2; pp. 446 - 454
• Main Authors: Yao, Yaobing, Wang, Weiwei, Jing, Lijun, Wang, Yiwen, Li, Mingzhe, Hou, Xiaocan, Wang, Jing, Peng, Tao, Teng, Junfang, Jia, Yanjie
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.02.2017; Springer Nature B.V
• Subjects: Animals; Animals, Newborn; Biochemistry; Biomedical and Life Sciences; Biomedicine; Brain Ischemia - genetics; Brain Ischemia - metabolism; Cell Biology; Cell Hypoxia - physiology; Gene Targeting - methods; Humans; Male; MicroRNAs - biosynthesis; MicroRNAs - genetics; Nerve Tissue Proteins - biosynthesis; Nerve Tissue Proteins - genetics; Neurochemistry; Neurology; Neurosciences; Original Paper; Rats; Rats, Sprague-Dawley; Cerebral ischemia; Let-7f; Hypoxic response; N-myc downstream-regulated gene-3 (NDRG3); microRNAs (miRNAs)
• ISSN: 0364-3190; 1573-6903; 1573-6903
• DOI: 10.1007/s11064-016-2091-x

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.