Gao Yakun, Hou Qiang, Guo Rong, Ying Jianghui, Xiong Jiachao, Jiang Hua
Department of Plastic Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, China.
Front Genet. 2022 Sep 26;13:998792. doi: 10.3389/fgene.2022.998792. eCollection 2022.
Sunlight exposure is an important environmental factor in the pathogenesis of skin cutaneous melanoma (SKCM). Ultraviolet (UV) from sunlight can cause excessive intracellular production of reactive oxygen species (ROS), resulting in damage from oxidative stress to cells. As a major iron-rich and ROS-producing organelle, mitochondria are considered as an important place for cell ferroptosis. Thus, the pathology and potential biological process of UV exposure-induced ferroptosis in the development of SKCM has aroused our strong interest. Gene expression profile datasets of melanoma cell line datasets (GSE31909) and UV-irradiated mitochondria dataset (GSE3632) were downloaded from the Gene Expression Omnibus (GEO) database, and ferroptosis-related genes were obtained from the FerrDb v2 database. After identifying the common differentially expressed genes (DEGs), comprehensive analyzes were performed, including functional annotation, protein-protein interaction (PPI) network construction, hub gene identification, and gene and tissue protein expression levels, survival analysis, and immune cell infiltration analysis. A total of 14 common DEGs was identified for subsequent analyses. Seven DEGs, including PSMB4, CRELD2, CDKN2A, TIMP1, NDRG1, ATF3 and JUND, have consistent performance in mRNA and protein expression in normal skin and SKCM tissues can be regarded as a good biomarker with SKCM diagnostic effectiveness. Functional enrichment analysis results indicate that HIF-1 signaling pathway and angiogenesis involved in the pathogenesis and development of SKCM. Induction of ferroptosis in tumor cells by enhancing the function of CD8 T cells is expected to be an effective intervention to promote tumor therapy. Our study reveals the pathogenesis and potential biological processes of UV exposure-induced ferroptosis in the development of SKCM, which may provide potential immunotherapy targets for SKCM treatment tumor cell ferroptosis mechanisms.
阳光照射是皮肤黑色素瘤(SKCM)发病机制中的一个重要环境因素。阳光中的紫外线(UV)可导致细胞内活性氧(ROS)过度产生,从而造成细胞受到氧化应激损伤。作为富含铁且产生ROS的主要细胞器,线粒体被认为是细胞铁死亡的重要场所。因此,紫外线照射诱导的铁死亡在SKCM发生发展中的病理及潜在生物学过程引起了我们浓厚的兴趣。从基因表达综合数据库(GEO)下载了黑色素瘤细胞系数据集(GSE31909)和紫外线照射线粒体数据集(GSE3632),并从FerrDb v2数据库中获取铁死亡相关基因。在鉴定出共同的差异表达基因(DEG)后,进行了综合分析,包括功能注释、蛋白质-蛋白质相互作用(PPI)网络构建、枢纽基因鉴定、基因和组织蛋白表达水平、生存分析以及免疫细胞浸润分析。共鉴定出14个共同的DEG用于后续分析。包括蛋白酶体亚基β4(PSMB4)、富含半胱氨酸的表皮生长因子样蛋白2(CRELD2)、细胞周期蛋白依赖性激酶抑制剂2A(CDKN2A)、金属蛋白酶组织抑制因子1(TIMP1)、N-myc下游调节基因1(NDRG1)、活化转录因子3(ATF3)和原癌基因蛋白Jun(JUND)在内的7个DEG在正常皮肤和SKCM组织中的mRNA和蛋白表达表现一致,可被视为具有SKCM诊断效能的良好生物标志物。功能富集分析结果表明,缺氧诱导因子-1(HIF-1)信号通路和血管生成参与了SKCM的发病机制和发展。通过增强CD8 T细胞功能诱导肿瘤细胞发生铁死亡有望成为促进肿瘤治疗的有效干预措施。我们的研究揭示了紫外线照射诱导的铁死亡在SKCM发生发展中的发病机制和潜在生物学过程,这可能为SKCM治疗提供潜在的免疫治疗靶点及肿瘤细胞铁死亡机制。