Hubei Bioinformatics & Molecular Imaging Key Laboratory, Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, College of Life Science and Technology, Huazhong University of Science and Technology, Luoyu Road 1037, Wuhan, 430074, China.
National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, 430074, China.
BMC Cancer. 2017 Dec 18;17(1):862. doi: 10.1186/s12885-017-3860-x.
Hepatocellular carcinoma (HCC) is the leading cause of cancer mortality. Chemical and virus induction are two major risk factors, however, the potential molecular mechanisms of their differences remain elusive. In this study, to identify the similarities and differences between chemical and virus induced HCC models, we compared the gene expression profiles between DEN and HBx mice models, as well as the differences among tumor, para-tumor and normal tissues.
We sequenced both gene and microRNA (miRNA) expression for HCC tumor tissues, para-tumor and normal liver tissues from DEN model mice (30-week-old) and downloaded the corresponding microarray expression data of HBx model from GEO database. Then differentially expressed genes (DEGs), miRNAs and transcription factors (TFs) were detected by R packages and performed functional enrichment analysis. To explore the gene regulatory network in HCC models, miRNA and TF regulatory networks were constructed by target prediction.
For model comparison, although DEGs between tumor and normal tissues in DEN and HBx models only had a small part of overlapping, they shared common pathways including lipid metabolism, oxidation-reduction process and immune process. For tissue comparisons in each model, genes in oxidation-reduction process were down-regulated in tumor tissues and genes in inflammatory response showed the highest expression level in para-tumor tissues. Genes highly expressed in both tumor and para-tumor tissues in two models mainly participated in immune and inflammatory response. Genes expressed in HBx model were also involved in cell proliferation and cell migration etc. Network analysis revealed that several miRNAs such as miR-381-3p, miR-142a-3p, miR-214-3p and TFs such as Egr1, Atf3 and Klf4 were the core regulators in HCC.
Through the comparative analyses, we found that para-tumor tissue is a highly inflammatory tissue while the tumor tissue is specific with both inflammatory and cancer signaling pathways. The DEN and HBx mice models have different gene expression pattern but shared pathways. This work will help to elucidate the molecular mechanisms underlying different HCC models.
肝细胞癌（HCC）是癌症死亡的主要原因。化学诱导和病毒诱导是两个主要的危险因素，然而，它们之间差异的潜在分子机制仍不清楚。在这项研究中，为了确定化学诱导和病毒诱导 HCC 模型之间的相似性和差异性，我们比较了 DEN 和 HBx 小鼠模型的基因表达谱，以及肿瘤、癌旁和正常组织之间的差异。
我们对 DEN 模型小鼠（30 周龄）的 HCC 肿瘤组织、癌旁组织和正常肝组织进行了基因和 microRNA（miRNA）表达测序，并从 GEO 数据库下载了相应的 HBx 模型的 microarray 表达数据。然后，使用 R 包检测差异表达基因（DEGs）、miRNAs 和转录因子（TFs），并进行功能富集分析。为了探索 HCC 模型中的基因调控网络，通过靶基因预测构建了 miRNA 和 TF 调控网络。
对于模型比较，尽管 DEN 和 HBx 模型中肿瘤组织与正常组织之间的 DEGs 仅有一小部分重叠，但它们共享包括脂质代谢、氧化还原过程和免疫过程在内的共同途径。对于每个模型中的组织比较，氧化还原过程中的基因在肿瘤组织中下调，炎症反应中的基因在癌旁组织中表达水平最高。在两个模型的肿瘤和癌旁组织中高表达的基因主要参与免疫和炎症反应。在 HBx 模型中表达的基因也参与细胞增殖和细胞迁移等过程。网络分析表明，miR-381-3p、miR-142a-3p、miR-214-3p 等几个 miRNA 和 Egr1、Atf3、Klf4 等 TF 是 HCC 的核心调控因子。
通过比较分析，我们发现癌旁组织是一种高度炎症性组织，而肿瘤组织则具有炎症和癌症信号通路的特异性。DEN 和 HBx 小鼠模型具有不同的基因表达模式，但共享途径。这项工作将有助于阐明不同 HCC 模型的分子机制。
