microRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4.
microRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4.
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microRNA-199a-3p 通过靶向 PDCD4 抑制肝细胞凋亡和肝癌发生。
DOI：
10.1038/s41389-020-00282-y
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发表时间：
2020-10-24
期刊：
影响因子：
6.2
通讯作者：
Hou J
中科院分区：
文献类型：
--
作者：
Li Z;Zhou Y;Zhang L;Jia K;Wang S;Wang M;Li N;Yu Y;Cao X;Hou J
肝细胞凋亡和肝脏炎症反应在炎症诱导的肝癌发生中起着重要作用。肝细胞凋亡调控的分子机制及其在肝癌发生中的作用已引起人们的广泛关注。一组microRNA（miRNAs）已被确定在肝细胞癌（HCC）中表达异常并参与肿瘤的进展，然而，这些表达异常的miRNAs在肝癌发生中的作用仍知之甚少。我们之前使用高通量测序分析了HCC中失调的miRNA，发现miR-199 a/B-3 p在人类正常肝脏中大量表达，而在HCC中显著降低，这促进了HCC的进展。miR-199 a/B-3 p是否参与HCC的发生发展至今仍不清楚。因此，本研究主要探讨miR-199 a/B-3 p在肝癌发生中的作用及其机制。在小鼠肝脏中检测到miR-199 a-2基因表达miR-199 a/B-3 p，并构建了miR-199 a-2基因敲除小鼠和肝细胞特异性miR-199 a-2基因敲除小鼠。肝细胞特异性miR-199 a-3 p敲除可显著增强二乙基亚硝胺（DEN）诱导的肝癌发生，这是由DEN诱导的肝细胞凋亡和肝损伤增强介导的。在对乙酰氨基酚（APAP）诱导的急性肝损伤模型中，肝细胞特异性miR-199 a-3 p敲除也加重了肝细胞凋亡。通过蛋白质组学筛选和报告基因验证，我们鉴定并验证了miR-199 a-3 p直接靶向促进细胞凋亡的肝细胞程序性死亡4（PDCD 4）。此外，我们证实miR-199 a-3 p通过靶向和抑制PDCD 4抑制肝细胞凋亡和肝损伤。因此，肝脏miR-199 a-3 p抑制肝细胞凋亡和肝癌发生，肝细胞中miR-199 a-3 p的减少可能会加剧肝损伤和肝癌的发展。
Hepatic apoptosis and the initiated liver inflammation play the initial roles in inflammation-induced hepatocarcinogenesis. Molecular mechanisms underlying the regulation of hepatocyte apoptosis and their roles in hepatocarcinogenesis have attracted much attention. A set of microRNAs (miRNAs) have been determined to be dysregulated in hepatocellular carcinoma (HCC) and participated in cancer progression, however, the roles of these dysregulated miRNAs in carcinogenesis are still poorly understood. We previously analyzed the dysregulated miRNAs in HCC using high-throughput sequencing, and found that miR-199a/b-3p was abundantly expressed in human normal liver while markedly decreased in HCC, which promotes HCC progression. Whether miR-199a/b-3p participates in HCC carcinogenesis is still unknown up to now. Hence, we focused on the role and mechanism of miR-199a/b-3p in hepatocarcinogenesis in this study. Hepatic miR-199a/b-3p was determined to be expressed by miR-199a-2 gene in mice, and we constructed miR-199a-2 knockout and hepatocyte-specific miR-199a-2 knockout mice. Diethylnitrosamine (DEN)-induced hepatocarcinogenesis were markedly increased by hepatocyte-specific miR-199a-3p knockout, which is mediated by the enhanced hepatocyte apoptosis and hepatic injury by DEN administration. In acetaminophen (APAP)-induced acute hepatic injury model, hepatocyte-specific miR-199a-3p knockout also aggravated hepatic apoptosis. By proteomic screening and reporter gene validation, we identified and verified that hepatic programed cell death 4 (PDCD4), which promotes apoptosis, was directly targeted by miR-199a-3p. Furthermore, we confirmed that miR-199a-3p-suppressed hepatocyte apoptosis and hepatic injury by targeting and suppressing PDCD4. Thus, hepatic miR-199a-3p inhibits hepatocyte apoptosis and hepatocarcinogenesis, and decreased miR-199a-3p in hepatocytes may aggravate hepatic injury and HCC development.
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影响因子：
50.3
作者：
Nakagawa H;Umemura A;Taniguchi K;Font-Burgada J;Dhar D;Ogata H;Zhong Z;Valasek MA;Seki E;Hidalgo J;Koike K;Kaufman RJ;Karin M
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DOI：
10.1186/s13046-019-1170-7
发表时间：
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DOI：
10.1152/ajpgi.00350.2018
发表时间：
2019-03-01
影响因子：
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作者：
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影响因子：
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作者：
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