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microRNA-199a-3p inhibits hepatic apoptosis and hepatocarcinogenesis by targeting PDCD4
Oncogenesis ( IF 5.9 ) Pub Date : 2020-10-24 , DOI: 10.1038/s41389-020-00282-y
Zhenyang Li , Ye Zhou , Liyuan Zhang , Kaiwei Jia , Suyuan Wang , Mu Wang , Nan Li , Yizhi Yu , Xuetao Cao , Jin Hou

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.



中文翻译:

microRNA-199a-3p通过靶向PDCD4抑制肝细胞凋亡和肝癌发生

肝细胞凋亡和引发的肝炎症在炎症诱导的肝癌发生中起着最初的作用。调节肝细胞凋亡及其在肝癌发生中的作用的分子机制已引起广泛关注。一组微小RNA(miRNA)已被确定在肝细胞癌(HCC)中失调并参与了癌症进展,但是,这些失调的miRNA在致癌作用中的作用仍然知之甚少。我们以前使用高通量测序分析了肝癌中失调的miRNA,发现miR-199a / b-3p在人正常肝脏中大量表达,而在肝癌中却明显降低,从而促进了肝癌的进展。迄今为止,miR-199a / b-3p是否参与HCC癌变尚不清楚。因此,在本研究中,我们重点研究了miR-199a / b-3p在肝癌发生中的作用和机制。确定肝miR-199a / b-3p表达为小鼠miR - 199a - 2基因,我们构建了miR - 199a - 2基因敲除和肝细胞特异性miR - 199a - 2剔除小鼠。肝细胞特异性miR-199a-3p敲除显着增加了二乙基亚硝胺(DEN)诱导的肝癌发生,这是由DEN给药增强的肝细胞凋亡和肝损伤介导的。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-199a-3p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,我们确定并验证了miR-199a-3p直接靶向肝程序性细胞死亡4(PDCD4),它可以促进细胞凋亡。此外,我们证实miR-199a-3p通过靶向和抑制PDCD4抑制肝细胞凋亡和肝损伤。因此,肝miR-199a-3p抑制肝细胞凋亡和肝癌发生,

更新日期:2020-10-28
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