Screening the expression of several miRNAs from TaqMan Low Density Array in traumatic brain injury: miR‐219a‐5p regulates neuronal apoptosis by modulating CCNA2 and CACUL1. Issue 2 (25th June 2019)

• Record Type: Journal Article
• Authors: Yan, Jing; Bu, Xiaomin; Li, Zhuoling; Wu, Jia; Wang, Cheng; Li, Dandan; Song, Jiaxi; Wang, Junjun
• Is Part Of: Journal of neurochemistry. Volume 150:Issue 2(2019)
• Page Start: 202
• Page End: 217
• Publication Date: 2019-06-25
• Subjects: biomarker -- CACUL1 -- CCNA2 -- microRNA -- miR‐219a‐5p -- traumatic brain injury; Neurochemistry -- Periodicals; 616.8042
• DOI: 10.1111/jnc.14717
• Languages: English
• ISSNs: 0022-3042

Abstract

Abstract: Circulating microRNAs (miRNAs) have emerged as diagnostic and prognostic biomarkers for traumatic brain injury (TBI). However, a comprehensive characterization of the serum miRNA profile in patients with TBI and the roles of these potential markers in neuronal regulation have rarely been reported. In this study, the levels of 754 serum miRNAs were initially determined in two pooled samples of 15 severe traumatic brain injury (sTBI) patients and 15 healthy controls using a TaqMan Low Density Array. The markedly upregulated miRNAs in sTBI patients were subsequently validated individually by quantitative reverse‐transcription PCR (RT‐qPCR) in another larger cohort consisting of 81 sTBI patients, 81 mild traumatic brain injury (mTBI) patients and 82 age/sex‐matched healthy controls. Seven miRNAs, including miR‐103a‐3p, miR‐219a‐5p, miR‐302d‐3p, miR‐422a, miR‐518f‐3p, miR‐520d‐3p and miR‐627, were significantly upregulated in both sTBI and mTBI patients compared with their expression in controls. Among these miRNAs, miR‐219a‐5p not only discriminated sTBI and mTBI patients from controls but also discriminated between sTBI and mTBI patients. We further show here that in the neuronal cell injury model, upregulated miR‐219a‐5p inhibits the expression of CCNA2 and CACUL1 and further regulates akt/Foxo3a and p53/Bcl‐2 signaling pathways, causing a notable change in the expression of cleaved caspase‐3, thereby inducing neuronal apoptosis. These results indicate that these seven selected miRNAs could serve as novel biomarkers for TBI. In particular, miR‐219a‐5p is a potentially valuable indicator of the diagnosis, prognosis of TBI and appears to regulate neuronal apoptosis and death. Abstract : Circulating microRNAs have emerged as diagnostic and prognostic biomarkers for traumatic brain injury (TBI). In this study, the levels of serum miRNAs were determined in severe traumatic brain injury patients. Expression profiles of seven miRNAs, including miR‐103a‐3p, miR‐219a‐5p, miR‐302d‐3p, miR‐422a, miR‐518f‐3p, miR‐520d‐3p and miR‐627, were significantly upregulated in TBI. Considering the level of miR‐219a‐5p associated with the severity and prognosis of TBI patient, we further investigated the role of miR‐219a‐5p in nerve injury. Our results demonstrate that up‐regulated miR‐219a‐5p may inhibit the expression of CCNA2 (cyclin‐A2) and CACUL1 (CDK2 Associated Cullin Domain 1), and further regulate the akt/Foxo3a and p53/Bcl‐2 signaling pathways in our neuronal cell injury model, causing expression levels of cleaved caspase‐3 to change, and thereby inducing neuronal apoptosis. Our findings do not only suggest that the selected serum miRNAs could be developed into useful diagnostic and predictable indicators for mTBI and sTBI but also provide mechanistic insight regarding that physiological and pathological progression of TBI.