Mechanism of Snhg8/miR-384/Hoxa13/FAM3A Axis Regulating Neuronal Apoptosis in Ischemic Mice Model

Jie Liu  ^{1   2   3} , Ping An  ^{4   5   6} , Yixue Xue  ^{4   5   6} , Dongfang Che  ^{1   2   3} , Xiaobai Liu  ^{1   2   3} , Jian Zheng  ^{1   2   3} , Yunhui Liu  ^{1   2   3} , Chunqing Yang  ^{1   2   3} , Zhen Li  ^{1   2   3} , Bo Yu  ^{7   8   9}

• ¹ Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China.
• ² Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China.
• ³ Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China.
• ⁴ Department of Neurobiology, College of Basic Medicine, China Medical University, Shenyang, China.
• ⁵ Key Laboratory of Cell Biology, Ministry of Public Health of China, China Medical University, Shenyang, China.
• ⁶ Key Laboratory of Medical Cell Biology, Ministry of Education of China, China Medical University, 110122, Shenyang, China.
• ⁷ Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang, China. yubo_sjhospital@sina.com.
• ⁸ Key Laboratory of Neuro-oncology in Liaoning Province, Shenyang, China. yubo_sjhospital@sina.com.
• ⁹ Liaoning Clinical Medical Research Center in Nervous System Disease, Shenyang, China. yubo_sjhospital@sina.com.

Abstract

Long noncoding RNAs, a subgroup of noncoding RNAs, are implicated in ischemic brain injury. The expression levels of Snhg8, miR-384, Hoxa13, and FAM3A were measured in chronic cerebral ischemia-induced HT22 cells and hippocampal tissues. The role of the Snhg8/miR-384/Hoxa13/FAM3A axis was evaluated in chronic cerebral ischemia models in vivo and in vitro. In this study, we found that Snhg8 and Hoxa13 were downregulated, while miR-384 was upregulated in chronic cerebral ischemia-induced HT22 cells and hippocampal tissues. Overexpression of Snhg8 and Hoxa13, and silencing of miR-384, all inhibited chronic cerebral ischemia-induced apoptosis of HT22 cells. Moreover, Snhg8 bound to miR-384 in a sequence-dependent manner and there was a reciprocal repression between Snhg8 and miR-384. Besides, overexpression of miR-384 impaired Hoxa13 expression by targeting its 3’UTR and regulated chronic cerebral ischemia-induced neuronal apoptosis. Hoxa13 bound to the promoter of FAM3A and enhanced its promotor activity, which regulated chronic cerebral ischemia-induced neuronal apoptosis. Remarkably, the in vivo experiments demonstrated that Snhg8 overexpression combined with miR-384 knockdown led to an anti-apoptosis effect. These results reveal that the Snhg8/miR-384/Hoxa13/FAM3A axis plays a critical role in the regulation of chronic cerebral ischemia-induced neuronal apoptosis.