School of Life Sciences, Zhengzhou University, Zhengzhou, 450001, China.
West China Biomedical Big Data Center, West China Hospital, Sichuan University, Chengdu, 610041, China.
Biol Sex Differ. 2024 Aug 22;15(1):64. doi: 10.1186/s13293-024-00638-8.
Sexual differences across molecular levels profoundly impact cancer biology and outcomes. Patient gender significantly influences drug responses, with divergent reactions between men and women to the same drugs. Despite databases on sex differences in human tissues, understanding regulations of sex disparities in cancer is limited. These resources lack detailed mechanistic studies on sex-biased molecules.
In this study, we conducted a comprehensive examination of molecular distinctions and regulatory networks across 27 cancer types, delving into sex-biased effects. Our analyses encompassed sex-biased competitive endogenous RNA networks, regulatory networks involving sex-biased RNA binding protein-exon skipping events, sex-biased transcription factor-gene regulatory networks, as well as sex-biased expression quantitative trait loci, sex-biased expression quantitative trait methylation, sex-biased splicing quantitative trait loci, and the identification of sex-biased cancer therapeutic drug target genes. All findings from these analyses are accessible on SexAnnoDB ( https://ccsm.uth.edu/SexAnnoDB/ ).
From these analyses, we defined 126 cancer therapeutic target sex-associated genes. Among them, 9 genes showed sex-biased at both the mRNA and protein levels. Specifically, S100A9 was the target of five drugs, of which calcium has been approved by the FDA for the treatment of colon and rectal cancers. Transcription factor (TF)-gene regulatory network analysis suggested that four TFs in the SARC male group targeted S100A9 and upregulated the expression of S100A9 in these patients. Promoter region methylation status was only associated with S100A9 expression in KIRP female patients. Hypermethylation inhibited S100A9 expression and was responsible for the downregulation of S100A9 in these female patients.
Comprehensive network and association analyses indicated that the sex differences at the transcriptome level were partially the result of corresponding sex-biased epigenetic and genetic molecules. Overall, SexAnnoDB offers a discipline-specific search platform that could potentially assist basic experimental researchers or physicians in developing personalized treatment plans.
分子水平上的性别差异深刻影响着癌症生物学和结果。患者的性别显著影响药物反应，男性和女性对同一种药物的反应不同。尽管有关于人类组织中性别差异的数据库，但对癌症中性别差异的调控机制了解有限。这些资源缺乏关于性别偏向分子的详细机制研究。
在这项研究中，我们对 27 种癌症类型进行了全面的分子差异和调控网络检查，深入研究了性别偏向的影响。我们的分析包括性别偏向的竞争性内源性 RNA 网络、涉及性别偏向 RNA 结合蛋白外显子跳跃事件的调控网络、性别偏向转录因子-基因调控网络以及性别偏向表达定量性状位点、性别偏向表达定量性状甲基化、性别偏向剪接定量性状位点和性别偏向癌症治疗药物靶点基因的鉴定。所有这些分析的结果都可以在 SexAnnoDB（https://ccsm.uth.edu/SexAnnoDB/）上获得。
从这些分析中，我们定义了 126 个癌症治疗靶点性别相关基因。其中，9 个基因在 mRNA 和蛋白质水平上都表现出性别偏向。具体来说，S100A9 是 5 种药物的靶点，其中钙已被 FDA 批准用于治疗结肠癌和直肠癌。转录因子（TF）-基因调控网络分析表明，SARC 男性组中的 4 个 TF 靶向 S100A9，并上调了这些患者中 S100A9 的表达。启动子区域甲基化状态仅与 KIRP 女性患者的 S100A9 表达相关。高甲基化抑制 S100A9 的表达，导致这些女性患者中 S100A9 的下调。
综合网络和关联分析表明，转录组水平的性别差异部分是相应性别偏向的表观遗传和遗传分子的结果。总体而言，SexAnnoDB 提供了一个特定于学科的搜索平台，有可能帮助基础实验研究人员或医生制定个性化的治疗计划。
