Department of Pathology and Laboratory MedicineUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA.
Department of SurgeryUniversity of Wisconsin School of Medicine and Public HealthMadisonWisconsinUSA.
Hepatol Commun. 2022 Aug;6(8):2170-2181. doi: 10.1002/hep4.1945. Epub 2022 Mar 28.
Dysregulation of expression of functional genes and pathways plays critical roles in the etiology and progression of hepatocellular carcinoma (HCC). Next generation-based RNA sequencing (RNA-seq) offers unparalleled power to comprehensively characterize HCC at the whole transcriptome level. In this study, 17 fresh-frozen HCC samples with paired non-neoplastic liver tissue from Caucasian patients undergoing liver resection or transplantation were used for RNA-seq analysis. Pairwise differential expression analysis of the RNA-seq data was performed to identify genes, pathways, and functional terms differentially regulated in HCC versus normal tissues. At a false discovery rate (FDR) of 0.10, 13% (n = 4335) of transcripts were up-regulated and 19% (n = 6454) of transcripts were down-regulated in HCC versus non-neoplastic tissue. Eighty-five Kyoto Encyclopedia of Genes and Genomes pathways were differentially regulated (FDR, <0.10), with almost all pathways (n = 83) being up-regulated in HCC versus non-neoplastic tissue. Among the top up-regulated pathways was oxidative phosphorylation (hsa00190; FDR, 1.12E-15), which was confirmed by Database for Annotation, Visualization, and Integrated Discovery (DAVID) gene set enrichment analysis. Consistent with potential oxidative stress due to activated oxidative phosphorylation, DNA damage-related signals (e.g., the up-regulated hsa03420 nucleotide excision repair [FDR, 1.14E-04] and hsa03410 base excision repair [FDR, 2.71E-04] pathways) were observed. Among down-regulated genes (FDR, <0.10), functional terms related to cellular structures (e.g., cell membrane [FDR, 3.05E-21] and cell junction [FDR, 2.41E-07], were highly enriched, suggesting compromised formation of cellular structure in HCC at the transcriptome level. Interestingly, the olfactory transduction (hsa04740; FDR, 1.53E-07) pathway was observed to be down-regulated in HCC versus non-neoplastic tissue, suggesting impaired liver chemosensory functions in HCC. Our findings suggest oxidative phosphorylation and the associated DNA damage may be the major driving pathologic feature in HCC.
功能基因和途径的表达失调在肝细胞癌（HCC）的病因和进展中起着关键作用。基于下一代的 RNA 测序（RNA-seq）在整个转录组水平上提供了全面描述 HCC 的无与伦比的能力。在这项研究中，使用了 17 个来自接受肝切除或移植的白种人患者的新鲜冷冻 HCC 样本和配对的非肿瘤性肝组织进行 RNA-seq 分析。对 RNA-seq 数据进行了成对差异表达分析，以鉴定 HCC 与正常组织中差异调节的基因、途径和功能术语。在错误发现率（FDR）为 0.10 时，与非肿瘤组织相比，HCC 中有 13%（n=4335）的转录本上调，19%（n=6454）的转录本下调。有 85 个京都基因与基因组百科全书途径差异调节（FDR，<0.10），几乎所有途径（n=83）在 HCC 与非肿瘤组织中均上调。上调最显著的途径之一是氧化磷酸化（hsa00190；FDR，1.12E-15），这通过数据库注释、可视化和综合发现（DAVID）基因集富集分析得到了证实。与激活的氧化磷酸化引起的潜在氧化应激一致，观察到与 DNA 损伤相关的信号（例如，上调的 hsa03420 核苷酸切除修复[FDR，1.14E-04]和 hsa03410 碱基切除修复[FDR，2.71E-04]途径）。在下调的基因中（FDR，<0.10），与细胞结构相关的功能术语（例如，细胞膜[FDR，3.05E-21]和细胞连接[FDR，2.41E-07]）高度富集，这表明在转录组水平上 HCC 中细胞结构的形成受损。有趣的是，嗅觉转导（hsa04740；FDR，1.53E-07）途径在 HCC 与非肿瘤组织中下调，表明 HCC 中肝脏化学感觉功能受损。我们的研究结果表明，氧化磷酸化和相关的 DNA 损伤可能是 HCC 的主要驱动病理特征。
