整合分析鉴定酒精性肝炎的关键基因、MicroRNAs 和潜在调控途径。

Identification of key genes, MicroRNAs and potentially regulated pathways in alcoholic hepatitis by integrative analysis.

机构信息

Clinical Laboratory of Traditional Chinese Medicine Hospital Affiliated to Southwest Medical University, Luzhou 646000, China.

Sichuan Luzhou Traditional Chinese Medicine Hospital, Luzhou 646000, China.

出版信息

Gene. 2019 Dec 15;720:144035. doi: 10.1016/j.gene.2019.144035. Epub 2019 Aug 9.

DOI:10.1016/j.gene.2019.144035

PMID:31404595

Abstract

Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease associated with high mortality. Current pharmacological treatment options are not fully effective, and novel target therapies are urgently needed. Until now, key genes, miRNAs and potential signaling pathways in AH remain unclear. Here, we integrated mRNA and miRNA expression profiles to reveal 1411 differentially expressed genes (DEG) and 69 differentially expressed miRNAs (DEM) in AH. And then 51 overlapping genes were identified by compared with miRNA target genes and DEGs, which named as consistent expression genes (CEGs). Pathway analysis showed that CEGs were mainly enriched in PI3K-Akt signaling pathway, MicroRNAs in cancer, FoxO signaling pathway, TNF signaling pathway and P53 signaling pathway. A total of 8 hub genes，FOS, FOXO1, SIRT1, ESR1, BCL2L11, CDK1, CCNB1 and CDKN1A, were screened using protein-protein interaction network analysis. In the regulatory network of miRNA and hub genes, a total of five miRNAs, miR-29c, miR-92b, miR-132, miR-221, miR-222, were identified as key miRNAs. Among them, miR-132 has been shown to target SIRT1, FOXO1, CDKN1A and BCL2L11, and miR-92b targets SIRT1 and BCL2L11. miR-221 and miR-222 both target FOS, ESR1, and BCL2L11. In addition, miR-29c is one of the major down-regulated miRNAs in AH, targeting FOS. Western blot analysis showed that SIRT1 and FoxO1 were expressed at low levels (P < 0.05) and CDK1 was highly expressed in the AH group (P < 0.05). The other five proteins were not significantly different between the two groups (P > 0.05). RT-PCR results showed that miR-132 was significantly higher in the AH group than in the normal group (P < 0.05), while miR-29c was lower than the normal group (P < 0.05), and the other three miRNAs were not significantly different between the two groups (P > 0.05). Therefore, SIRT1, FOXO1, CDK1, miR-132 and miR-29c are involved in the regulation of FoxO and P53 signaling pathways, cell cycle and other biological processes, which may play a key role in the pathogenesis of AH.

摘要

酒精性肝炎 (AH) 是一种与高死亡率相关的严重的酒精性肝病。目前的药物治疗选择并不完全有效，因此迫切需要新的靶向治疗方法。到目前为止，AH 中的关键基因、miRNA 和潜在信号通路仍不清楚。在这里，我们整合了 mRNA 和 miRNA 表达谱，揭示了 AH 中 1411 个差异表达基因 (DEG) 和 69 个差异表达 miRNA (DEM)。然后通过与 miRNA 靶基因和 DEGs 比较，鉴定出 51 个重叠基因，命名为一致表达基因 (CEGs)。通路分析表明，CEGs 主要富集在 PI3K-Akt 信号通路、癌症中的 miRNA、FoxO 信号通路、TNF 信号通路和 P53 信号通路。使用蛋白质-蛋白质相互作用网络分析共筛选出 8 个枢纽基因，FOS、FOXO1、SIRT1、ESR1、BCL2L11、CDK1、CCNB1 和 CDKN1A。在 miRNA 和枢纽基因的调控网络中，共鉴定出 5 个关键 miRNA，miR-29c、miR-92b、miR-132、miR-221 和 miR-222。其中，miR-132 已被证明靶向 SIRT1、FOXO1、CDKN1A 和 BCL2L11，而 miR-92b 靶向 SIRT1 和 BCL2L11。miR-221 和 miR-222 均靶向 FOS、ESR1 和 BCL2L11。此外，miR-29c 是 AH 中主要下调的 miRNA 之一，靶向 FOS。Western blot 分析表明，SIRT1 和 FoxO1 表达水平较低（P < 0.05），而 CDK1 在 AH 组中高表达（P < 0.05）。其他五种蛋白质在两组之间无显著差异（P > 0.05）。RT-PCR 结果表明，与正常组相比，AH 组 miR-132 显著升高（P < 0.05），而 miR-29c 显著降低（P < 0.05），其他三种 miRNA 在两组间无显著差异（P > 0.05）。因此，SIRT1、FOXO1、CDK1、miR-132 和 miR-29c 参与 FoxO 和 P53 信号通路、细胞周期等生物学过程的调控，可能在 AH 的发病机制中起关键作用。