Aberrant expression of miRNA-192-5p contributes to N,N-dimethylformamide-induced hepatic apoptosis |
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Authors: | Zhen Zhang Wei Zhu Ziqi Liu Ye Liu Chong Chang Hongmei Jiang Ruobi Li Yongmei Xiao Wen Chen Qiansheng Hu Qing Wang |
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Institution: | 1. Department of Toxicology, School of Public Health, Sun Yat-sen University, Guangzhou, China;2. Department of Toxicology, Guangzhou Center for Disease Control and Prevention, Guangzhou, China;3. Department of Occupational and Environmental Health, School of Public Health, Sun Yat-sen University, Guangzhou, China |
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Abstract: | Excessive exposure to N,N-dimethylformamide (DMF) can lead to occupational liver poisoning in workers; however, the underlying mechanism is not fully clarified. The importance of microRNAs (miRNAs) in chemical-induced hepatotoxicity has been demonstrated. To determine whether miRNAs are also involved in DMF-induced hepatotoxicity, we systematically analyzed the miRNA expression profiles in DMF-treated (75 and 150 mm ) HL-7702 liver cells and controls by high-throughput sequencing. Among the altered miRNAs, miR-192-5p was the most significantly upregulated in HL-7702 cells after DMF exposure and was involved in DMF-mediated cell apoptosis. By contrast, suppression of miR-192-5p in HL-7702 cells attenuated the apoptosis induced by DMF. Furthermore, the anti-apoptotic gene (NIN1/RPN12 binding protein 1 homolog NOB1]) was predicted to be a potential miR-192-5p target according to bioinformatics analysis. The direct interaction between miR-192-5p and NOB1 was confirmed by the dual-luciferase activity assay in HEK293FT cells. Overexpression of miR-192-5p efficiently reduced NOB1 mRNA and protein expression in HL-7702 cells. Alteration in NOB1 expression influenced DMF-induced hepatotoxicity by affecting hepatic apoptosis. In addition, the inverse correlation between miR-192-5p expression levels and NOB1 expression was further confirmed in DMF-exposed mouse liver tissue samples. These observations demonstrated that promotion of apoptosis from the suppression of NOB1 by miR-192-5p overexpression was responsible for the DMF-induced hepatotoxicity. This work provides the molecular mechanism at the miRNA level for hepatic apoptosis induced by DMF. |
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Keywords: | apoptosis hepatotoxicity miRNA-192-5p N N-dimethylformamide NOB1 |
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