Gene expression network related to DNA methylation and miRNA regulation during the process of aflatoxin B1-induced malignant transformation of L02 cells
Gene expression network related to DNA methylation and miRNA regulation during the process of aflatoxin B1-induced malignant transformation of L02 cells
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黄曲霉毒素B1诱导L02细胞恶性转化过程中DNA甲基化和miRNA调控相关基因表达网络
DOI：
10.1002/jat.4233
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发表时间：
2021-09-24
影响因子：
3.3
通讯作者：
Liu，Wen-Bin
中科院分区：
文献类型：
--
作者：
Zhao，Ji;Chen，Hong-Qiang;Liu，Wen-Bin
黄曲霉毒素是由黄曲霉、寄生曲霉和其他真菌通过聚酮途径分泌的次级代谢产物，在许多食物中都可以检测到。黄曲霉毒素具有很强的毒性和致癌性，许多研究表明黄曲霉毒素与肝癌高度相关。本研究以黄曲霉毒素B1（AFB 1）诱导L02细胞恶性转化，采用高通量测序技术检测AFB 1诱导的L02细胞基因表达、miRNA表达及甲基化水平。基因和miRNA表达结果显示，与DMSO组相比，AFB 1处理组中有2547个基因和315个miRNA发生变化。其中RSAD 2和SCIN表达显著上调，TRAPPC 3和UBE 2L 6表达显著下调。Has-miR-33 b-3 p显著上调，而Has-miR-3613 - 5 p显著下调。甲基化结果显示，DNMT 3a和DNMT 3b基因的启动子或编码DNA序列（CDS）上有2832个CpG位点发生甲基化，DNMT 3a和DNMT 3b基因的表达显著上调。此外，在TRAPPC 3L、CDH 13和SPINK 13中发生了高甲基化。GO和KEGG通路分析结果显示，显著改变的基因和miRNAs主要参与肿瘤的形成、增殖、侵袭和迁移。网络图谱分析结果显示，Hsa-miR-3613 - 5 p、Hsa-miR-615 - 5 p、Hsa-miR-615 - 3 p和Hsa-miR-3158 - 3 p是AFB 1诱导L02细胞恶性转化的关键miRNAs。此外，ONECUT 2、RAP 1GAP 2和FSTL 4的表达受DNA甲基化和miRNA的调控。这些结果表明，由DNA甲基化和miRNA调控的基因表达网络可能在AFB 1诱导的肝细胞癌中起重要作用。
Aflatoxin is a secondary metabolite secreted byAspergillus flavus, parasiticAspergillus, and other fungi through the polyketone pathway, and it can be detected in many foods. Aflatoxin has strong toxicity and carcinogenicity, and many studies have shown that aflatoxin is highly associated with liver cancer. In the present study, malignant transformation of L02 cells was induced by aflatoxin B1 (AFB1), and the gene expression, miRNA expression, and methylation level were detected by high‐throughput sequencing. The gene and miRNA expression results showed that 2547 genes and 315 miRNAs were changed in the AFB1‐treated group compared with the DMSO group. Among them,RSAD2andSCINwere significantly upregulated, whereasTRAPPC3LandUBE2L6were significantly downregulated. Has‐miR‐33b‐3p was significantly upregulated, whereas Has‐miR‐3613‐5p was significantly downregulated. The methylation results showed that 2832 CpG sites were methylated on the promoter or coding DNA sequence (CDS) of the gene, whereas the expression ofDNMT3aandDNMT3bwas significantly upregulated. Moreover, hypermethylation occurred inTRAPPC3L,CDH13, andSPINK13. The results of GO and KEGG pathway analyses showed that significantly changed genes and miRNAs were mainly involved in tumor formation, proliferation, invasion, and migration. The results of network map analysis showed that Hsa‐miR‐3613‐5p, Hsa‐miR‐615‐5p, Hsa‐miR‐615‐3p, and Hsa‐miR‐3158‐3p were the key miRNAs for malignant transformation of L02 cells induced by AFB1. In addition, the expression ofONECUT2,RAP1GAP2, andFSTL4was regulated by DNA methylation and miRNAs. These results suggested that the gene expression network regulated by DNA methylation and miRNAs may play a vital role in AFB1‐induced hepatocellular carcinoma.