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基于组学技术鉴定致癌物诱导肝癌发生过程中的共享途径和性别差异途径:Dlk1-Dio3基因组印记区域的重要作用

Omics-Based Identification of Shared and Gender Disparity Routes in -Induced Hepatocarcinogenesis: An Important Role for Dlk1-Dio3 Genomic Imprinting Region.

作者信息

Zhang Jing, Li Huiling, Dong Jianyi, Zhang Nan, Liu Yang, Luo Xiaoqin, Chen Jun, Wang Jingyu, Wang Aiguo

机构信息

Department of Comparative Medicine, Laboratory Animal Center, Dalian Medical University, Dalian, China.

出版信息

Front Genet. 2021 May 31;12:620594. doi: 10.3389/fgene.2021.620594. eCollection 2021.

Abstract

The phenomenon of gender disparity is very profound in hepatocellular carcinoma (HCC). Although previous research has revealed important roles of microRNA (miRNA) in HCC, there are no studies investigating the role of miRNAs in gender disparity observed hepatocarcinogenesis. In the present study, we investigated the global miRNAomics changes related to -induced male-prevalent hepatocarcinogenesis in a -transgenic mouse model (-Tg) by next-generation sequencing (NGS). We identified shared by also unique changes in miRNA expression profiles in gender-dependent hepatocarcinogenesis. Two hundred sixty-four differentially expressed miRNAs (DEMIRs) with value ≤0.05 and fold change ≥2 were identified. A vertical comparison revealed that the lower numbers of DEMIRs in the hepatic tumor (T) compared with the peri-tumor precancerous tissue (P) of -Tg and normal liver tissue of wild-type C57BL/6J mice (W) in males indicated that males are more susceptible to develop HCC. The expression pattern analysis revealed 43 common HCC-related miRNAs and 4 -positive-related miRNAs between males and females. By integrating the mRNA transcriptomic data and using 3-node FFL analysis, a group of significant components commonly contributing to HCC between sexes were filtered out. A horizontal comparison showed that the majority of DEMIRs are located in the Dlk1-Dio3 genomic imprinting region (GIR) and that they are closely related to not only hepatic tumorigenesis but also to gender disparity in hepatocarcinogenesis. This is achieved by regulating multiple metabolic pathways, including retinol, bile acid, and steroid hormones. In conclusion, the identification of shared and gender-dependent DEMIRs in hepatocarcinogenesis provides valuable insights into the mechanisms that contribute to male-biased -induced hepatic carcinogenesis.

摘要

肝细胞癌(HCC)中性别差异现象非常显著。尽管先前的研究揭示了微小RNA(miRNA)在HCC中的重要作用,但尚无研究调查miRNA在性别差异相关的肝癌发生中的作用。在本研究中,我们通过下一代测序(NGS)在一种转基因小鼠模型(-Tg)中研究了与诱导雄性为主的肝癌发生相关的整体miRNA组学变化。我们在性别依赖性肝癌发生中鉴定出了miRNA表达谱中的共同变化以及独特变化。鉴定出264个差异表达的miRNA(DEMIRs),其值≤0.05且变化倍数≥2。纵向比较显示,在雄性中,与-Tg的肝肿瘤(T)相比,其肿瘤周围癌前组织(P)以及野生型C57BL/6J小鼠(W)的正常肝组织中DEMIRs数量较少,这表明雄性更容易发生HCC。表达模式分析揭示了雄性和雌性之间43个常见的HCC相关miRNA和4个与阳性相关的miRNA。通过整合mRNA转录组数据并使用3节点FFL分析,筛选出了一组在两性中共同导致HCC的重要成分。横向比较表明大多数DEMIRs位于Dlk1-Dio3基因组印记区域(GIR),并且它们不仅与肝肿瘤发生密切相关,还与肝癌发生中的性别差异密切相关。这是通过调节多种代谢途径实现的,包括视黄醇、胆汁酸和类固醇激素。总之,在肝癌发生中鉴定出共同的和性别依赖性的DEMIRs为导致雄性偏向的诱导性肝癌发生的机制提供了有价值的见解。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/9bae/8202007/31c2faaf9a9c/fgene-12-620594-g001.jpg

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