Department of Infectious Diseases, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, Xi'an, Shaanxi 710061, P.R. China.
Oncol Rep. 2019 Sep;42(3):937-952. doi: 10.3892/or.2019.7217. Epub 2019 Jun 28.
Hepatocellular carcinoma (HCC) is sexually disparate in humans, with a significantly increased prevalence in males. The molecular mechanisms by which the inhibition or development of liver cancer are facilitated require further investigation with regard to sex factors affecting disease progression. In the present study, functional signatures of differentially expressed genes (DEGs) were screened in female and male tumors via bioinformatics analysis. The following gene chip expression profiles were downloaded from the Gene Expression Omnibus: GSE19665, GSE23342 and GSE9843. They comprised cancerous and non‑cancerous tissue from patients with HCC and included critical sex features. Further evaluation of selected DEGs in the two sexual groups was performed via hierarchical clustering analysis. Venn diagram and functional protein‑protein interaction (PPI) network analyses were performed. Survival analysis of patients with differences in gene expression levels was subsequently performed using the Kaplan‑Meier Plotter database. Certain identified DEGs were common in female and male tumor samples, whereas others exhibited a sexually‑biased expression profile. Gene Ontology revealed that the cell cycle module 'biological process' was enriched in tumors derived from both sexes, whereas the metabolic pathways and drug metabolism modules were only significantly enriched in cancer tissues from male subjects. A number of hub DEGs in the cell cycle and p53 signaling pathways were involved in significant protein‑protein interaction (PPI) modules, including CDK1 and CCNB1. These DEGs were upregulated in tumors derived from female subjects compared with those derived from male subjects, and could be used as markers of poor prognosis in male patients. Other genes, such as CYP3A4 and SERPINA4, were identified in metabolic pathways, and were downregulated in male compared with female subjects. These genes were associated with a decreased survival rate. The data demonstrated that sex differences in physiology may regulate the levels of gene expression and/or activity, including gene function associated with oncogenesis and the outcomes of liver cancer. Additional surveys are required to explore in detail the molecular mechanisms underlying the differences in gene expression between the two sexes during the development of liver cancer.
肝细胞癌（HCC）在人类中存在性别差异，男性的患病率明显增加。需要进一步研究影响疾病进展的性别因素，以了解抑制或发展肝癌的分子机制。本研究通过生物信息学分析筛选了女性和男性肿瘤中差异表达基因（DEG）的功能特征。从基因表达综合数据库中下载了以下基因芯片表达谱：GSE19665、GSE23342 和 GSE9843。它们包含来自 HCC 患者的癌症和非癌症组织，并包含关键的性别特征。通过层次聚类分析进一步评估了这两个性别的选定 DEG。进行了 Venn 图和功能蛋白质-蛋白质相互作用（PPI）网络分析。随后使用 Kaplan-Meier Plotter 数据库对基因表达水平存在差异的患者进行了生存分析。某些鉴定的 DEG 在女性和男性肿瘤样本中是共同的，而其他 DEG 则表现出性别偏向的表达模式。基因本体论揭示，细胞周期模块“生物过程”在来自两性的肿瘤中均被富集，而代谢途径和药物代谢模块仅在来自男性的肿瘤组织中显著富集。细胞周期和 p53 信号通路中的一些关键 DEG 参与了显著的蛋白质-蛋白质相互作用（PPI）模块，包括 CDK1 和 CCNB1。与男性来源的肿瘤相比，这些 DEG 在女性来源的肿瘤中上调，可作为男性患者预后不良的标志物。其他基因，如 CYP3A4 和 SERPINA4，在代谢途径中被鉴定出，并且在男性中下调与女性相比。这些基因与存活率降低有关。数据表明，生理性别差异可能调节基因表达和/或活性水平，包括与肿瘤发生和肝癌结局相关的基因功能。需要进行更多的调查来详细探讨在肝癌发生过程中两性之间基因表达差异的分子机制。
