多组学分析预测双硫死亡相关基因在肾透明细胞癌中的作用  

A Multi-omics analysis of disulfidoptosis related genes and its role in clear cell renal cell carcinoma

作　　者：努尔艾合麦提·依明尼依孜 周洪民 高宇宸 董云则 刘帅 谢天承 许云飞[1,2] NURAIHEMAITI·Yimingniyizi;ZHOU Hongmin;GAO Yuchen;DONG Yunze;LIU Shuai;XIE Tiancheng;XU Yunfei(School of Medicine,Tongji University,Shanghai 200092,China;Department of Urology,Shanghai Tenth People's Hospital,School of Medicine,Tongji University,Shanghai 200072,China;Department of Urology,Kashgar Prefecture Second People s Hospital of Xinjiang Uygur Autonomous Region,Kashgar 844000,Xinjiang Uygur Autonomous Region,China)

机构地区：[1]同济大学医学院,上海200092 [2]同济大学附属第十人民医院泌尿外科,上海200072 [3]新疆维吾尔自治区喀什地区第二人民医院泌尿外科,新疆喀什844000

出　　处：《同济大学学报（医学版）》2024年第5期665-679,共15页Journal of Tongji University(Medical Science)

基　　金：上海申康医院发展中心临床科技创新项目(SHDC22020207)。

摘　　要：目的肾透明细胞癌的肿瘤微环境与双硫死亡之间的关系尚不明确,本研究旨在探索双硫死亡相关基因在肾透明细胞癌中的作用。方法选择15个双硫死亡相关基因,并且使用癌症基因组图谱肾透明细胞癌数据库、单细胞RNA测序、单细胞空间RNA-seq、基因突变、预后影响、通路富集、药物敏感性和体外实验来表征它们的表达谱。结果肿瘤微环境分析显示C1和C2亚型之间存在不同的免疫浸润和突变模式,且C1患者预后较差。发现5个双硫死亡相关基因(SLC7A11,ACTN4,IQGAP1,ACTB和DSTN)是肾透明细胞癌的独立预后因素。其中,DSTN是最有效的肿瘤抑制基因,在肿瘤样本中显著下调,尤其在癌相关成纤维细胞中明显下调。单细胞药物敏感性分析显示,DSTN high的癌相关成纤维细胞表现出较强的药物敏感性。最后,本研究证实了DSTN在肾透明细胞癌组织及细胞系中的异常下调。结论DSTN可能是肾透明细胞癌潜在的诊断和治疗靶点。Objective To investigate the roles of disulfidoptosis-related genes(DRGs)in clear cell renal cell carcinoma(ccRCC).Methods Based on results of the previous study,15 DRGs were selected.Expression profiles of DRGs were characterized in TCGA-KIRC,scRNA-seq,stRNA-seq,genetic mutation,prognostic implications,pathway enrichment and drug sensitivity,then verified by experimental study.Results The immune microenvironment analyses revealed that there was different immune infiltration and mutation patterns between C1 and C2 subtypes,and patients with C1 subtype had poorer prognosis.A DRGs related signature including SLC7A11,ACTN4,IQGAP1,ACTB,and DSTN was established,and considered as an independent prognostic factor for ccRCC.Among the DRGs,DSTN was the most potential tumor suppressor gene,which was downregulated in tumor sample,especially in cancer-associated fibroblasts(CAFs).And single-cell drug sensitivity analyses found that CAFs with DSTN high exhibited relatively stronger drug sensitivity.Finally,an abnormal downregulation of DSTN in ccRCC tissues and cell lines was observed.Conclusion The study suggests that disulfidoptosis-related gene DSTN might serve as a potential diagnostic and therapeutic target for ccRCC.

关 键 词：肾细胞癌 双硫死亡 单细胞基因组学 癌相关成纤维细胞 

分 类 号：R737.11[医药卫生—肿瘤]