Screening of Candidate Inflammatory Markers of Epithelial Cells in Hepatocellular Carcinoma Based on Integration Analysis of TCGA/ICGC Databases and Single-cell Sequencing.

Zupin Huang, Zhuokai Li, Xinliang Lv, Wei Tan
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Abstract

Background: Hepatocellular Carcinoma (HCC) is closely linked to inflammatory reactions, with chronic liver diseases acting as major risk factors. In the inflammatory microenvironment, repeated damage and repair of liver cells lead to genetic mutations, abnormal proliferation, and tumorigenesis.

Objective: This study aimed to investigate the expression profile of specific cell clusters under inflammatory stimulation in HCC and identify potential therapeutic drugs.

Methods: Comprehensive analysis of HCC transcriptome data and single-cell sequencing data from TCGA, ICGC, and GEO databases was conducted to explore the specific molecular mechanisms of epithelial cells. Virtual screening of natural compounds in the ZINC database and in vitro cell experiments were performed to identify drugs that regulate the expression of inflammatory factors in epithelial cells.

Results: Analysis of the single-cell dataset revealed cell clusters closely associated with HCC, notably Epithelial cells, Hepatocytes, MSC, and iPS cells, with Epithelial cells playing a pivotal role in HCC development. Further investigation of TCGA data unveiled 83 differentially expressed genes (DEGs) related to inflammatory responses in HCC. Intersection analysis of DEGs in epithelial cells and HCC DEGs identified 12 common DEGs, including ADRM1, ATP2B1, FZD5, GPC3, KIF1B, KLF6, LY6E, MET, NAMPT, SERPINE1, SPHK1, and SRI. Prognostic analysis revealed that CCL7, GPR132, ITGB8, PTAFR, SELL, and VIP were influential in the survival prognosis of HCC. A prognostic model based on the expression levels of these genes demonstrated an increased risk of HCC associated with higher differential expression of inflammatory response genes. Additionally, molecular dynamics simulations indicated that compounds NADH and Deferoxamine formed stable docking models with the inflammatory protein VIP, suggesting their potential as candidates for targeted therapy.

Conclusion: Inflammatory factors CCL7, GPR132, ITGB8, PTAFR, SELL, and VIP influence the inflammatory cascade response in HCC epithelial cells, and their expression correlates with the survival prognosis of HCC patients. Interfering with VIP expression effectively suppresses proliferation, migration, and invasion of HCC cells, as well as inhibiting the occurrence of inflammatory cascade reactions, thus slowing down the progression of hepatocellular carcinoma. Furthermore, compounds NADH and Deferoxamine have the potential to target and bind to the inflammatory protein VIP, highlighting their relevance in potential HCC treatment.

基于 TCGA/ICGC 数据库和单细胞测序的整合分析筛选肝细胞癌上皮细胞的候选炎症标记物
背景:肝细胞癌(HCC)与炎症反应密切相关,慢性肝病是其主要风险因素。在炎症微环境中,肝细胞的反复损伤和修复导致基因突变、异常增殖和肿瘤发生:本研究旨在调查 HCC 炎症刺激下特定细胞群的表达谱,并确定潜在的治疗药物:方法:综合分析HCC转录组数据和来自TCGA、ICGC和GEO数据库的单细胞测序数据,探索上皮细胞的特定分子机制。对 ZINC 数据库中的天然化合物进行虚拟筛选,并进行体外细胞实验,以确定能调节上皮细胞中炎症因子表达的药物:对单细胞数据集的分析发现了与HCC密切相关的细胞群,特别是上皮细胞、肝细胞、间充质干细胞和iPS细胞,其中上皮细胞在HCC的发展中起着关键作用。对 TCGA 数据的进一步研究发现了 83 个与 HCC 炎症反应相关的差异表达基因(DEGs)。上皮细胞中的 DEGs 与 HCC DEGs 的交叉分析发现了 12 个常见的 DEGs,包括 ADRM1、ATP2B1、FZD5、GPC3、KIF1B、KLF6、LY6E、MET、NAMPT、SERPINE1、SPHK1 和 SRI。预后分析表明,CCL7、GPR132、ITGB8、PTAFR、SELL 和 VIP 对 HCC 的生存预后有影响。基于这些基因表达水平的预后模型表明,炎症反应基因的差异表达越高,患 HCC 的风险就越大。此外,分子动力学模拟表明,化合物 NADH 和去铁胺与炎症蛋白 VIP 形成了稳定的对接模型,表明它们有可能成为靶向治疗的候选药物:结论:炎症因子CCL7、GPR132、ITGB8、PTAFR、SELL和VIP影响着HCC上皮细胞的炎症级联反应,它们的表达与HCC患者的生存预后相关。干扰 VIP 的表达可有效抑制 HCC 细胞的增殖、迁移和侵袭,并抑制炎症级联反应的发生,从而减缓肝细胞癌的进展。此外,NADH 和去铁胺化合物具有靶向和结合炎症蛋白 VIP 的潜力,突出了它们在潜在的 HCC 治疗中的相关性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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