Deregulation of the Genes that Are Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Hepatocellular Carcinoma
Deregulation of the Genes that Are Involved in Drug Absorption, Distribution, Metabolism, and Excretion in Hepatocellular Carcinoma
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DOI：
10.1124/jpet.118.255018
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发表时间：
2019-03-01
影响因子：
3.5
通讯作者：
Meech, Robyn
中科院分区：
文献类型：
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作者：
Hu, Dong Gui;Marri, Shashikanth;Meech, Robyn
参与药物吸收、分布、代谢和排泄（ADME）的基因称为ADME基因。目前，298个编码I相和II相药物代谢酶、转运蛋白和修饰剂的基因被PharmaADME联盟指定为ADME基因。ADME基因在肝脏中高度表达，其水平可受肝脏疾病如肝细胞癌（HCC）的影响。本研究通过The Cancer Genome Atlas肝癌项目获取了371例肝癌患者的RNA测序和microRNA（miRNA）测序数据，并进行了ADME基因靶向差异基因表达分析和表达相关性分析。298个ADME基因中有233个（78%）在HCC中表达。在这些基因中，几乎四分之一（58个基因）显著下调，而相对于健康肝脏，HCC中只有6%（15个）上调。此外，一半（14/28）的核心ADME基因（CYP 1A 2、CYP 2A 6、CYP 2B 6、CYP 2C 8、CYP 2C 9、CYP 2C 19、CYP 2 E1、CYP 3A 4、NAT 1、NAT 2、UGT 2B 7、SLC 22 A1、SLCO 1B 1和SLCO 1B 3）下调。此外，大约一半的核心ADME基因彼此正相关，并且与称为ADME修饰因子的转录因子正相关（AHR、ARNT、HNF 4A、PXR、CAR、PPARA和RXRA）或负相关（PPARD和PPARG）。最后，我们发现大多数已知调节核心ADME基因的miRNA在HCC中上调。总的来说，这些数据揭示了1）肝脏中广泛的转录因子介导的ADME共表达网络，其有效地协调内源性和外源性化合物的代谢和消除;和2）HCC中该网络的广泛失调，最可能是由于转录和转录后（miRNA）途径的失调。
Genes involved in drug absorption, distribution, metabolism, and excretion (ADME) are called ADME genes. Currently, 298 genes that encode phase I and II drug metabolizing enzymes, transporters, and modifiers are designated as ADME genes by the PharmaADME Consortium. ADME genes are highly expressed in the liver and their levels can be influenced by liver diseases such as hepatocellular carcinoma (HCC). In this study, we obtained RNA-sequencing and microRNA (miRNA)-sequencing data from 371 HCC patients via The Cancer Genome Atlas liver hepatocellular carcinoma project and performed ADME gene-targeted differential gene expression analysis and expression correlation analysis. Two hundred thirty-three of the 298 ADME genes (78%) were expressed in HCC. Of these genes, almost one-quarter (58 genes) were significantly downregulated, while only 6% (15) were upregulated in HCC relative to healthy liver. Moreover, one-half (14/28) of the core ADME genes (CYP1A2, CYP2A6, CYP2B6, CYP2C8, CYP2C9, CYP2C19, CYP2E1, CYP3A4, NAT1 , NAT2, UGT2B7, SLC22A1, SLCO1B1 , and SLCO1B3) were downregulated. In addition, about one-half of the core ADME genes were positively correlated with each other and were also positively (AHR, ARNT, HNF4A, PXR, CAR, PPARA, and RXRA) or negatively (PPARD and PPARG) correlated with transcription factors known as ADME modifiers. Finally, we show that most miRNAs known to regulate core ADME genes are upregulated in HCC. Collectively, these data reveal 1) an extensive transcription factor-mediated ADME coexpression network in the liver that efficiently coordinates the metabolism and elimination of endogenous and exogenous compounds; and 2) a widespread deregulation of this network in HCC, most likely due to deregulation of both transcriptional and post-transcriptional (miRNA) pathways.