Yue Zhanghui, Sun Jianfang, Shi Liqing
Institute of Dermatology, Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, China.
Front Genet. 2022 May 25;13:887542. doi: 10.3389/fgene.2022.887542. eCollection 2022.
Ferroptosis is a newly discovered form of non-apoptotic cell death that relies on iron-mediated oxidative damage, playing a crucial role in the progression and therapy resistance of melanoma. Hence, the potential value of ferroptosis-related genes (FRGs) as a prognostic model and therapeutic target in melanoma requires further investigation. In this study, the relationship between FRGs and melanoma was revealed by analyzing the mRNA expression profiles from The Cancer Genome Atlas (TCGA) and Gene Expression Synthesis (GEO). A 6-FRGs signature was constructed by Univariate, multivariate, and lasso Cox regression analyses in the TCGA cohort. The GEO database was used to validate the efficacy of the signature. The protein and mRNA expression level of the signature genes were examined in real-world melanoma tissues via immunohistochemical and quantificational real-time polymerase chain reaction (qRT-PCR). Functional enrichment analysis and immune-related analysis were conducted to identify the potential biological functions and pathways of the signature. Ten putative small molecule drugs were predicted by Connectivity Map (CMAP). As a result, a 6-FRGs signature was constructed to stratify melanoma patients into two risk groups. Compared with the low-risk group, patients in the high-risk group had a worse prognosis and a lower ImmuneScore. Immune-related pathways were enriched in the low-risk group. Immune Function and immune cell infiltration of the low-risk group were significantly higher than that of the high-risk group. The differential expression of these six FRGs in melanoma and adjacent normal tissues was confirmed. Moreover, higher expression of immune checkpoint molecules and a greater sensitivity to immunotherapy were observed in the low-risk group. Some small molecular drugs in the CMAP database hold the potential to treat melanoma. Overall, we identified a novel FRGs signature for prognostic prediction in melanoma. Based on the signature-related immune infiltration landscape found in our study, targeting the FRGs might be a therapeutic alternative for melanoma.
铁死亡是一种新发现的非凋亡性细胞死亡形式，依赖于铁介导的氧化损伤，在黑色素瘤的进展和治疗耐药性中起关键作用。因此，铁死亡相关基因（FRGs）作为黑色素瘤预后模型和治疗靶点的潜在价值需要进一步研究。在本研究中，通过分析来自癌症基因组图谱（TCGA）和基因表达综合数据库（GEO）的mRNA表达谱，揭示了FRGs与黑色素瘤之间的关系。在TCGA队列中，通过单变量、多变量和套索Cox回归分析构建了一个由6个FRGs组成的特征。利用GEO数据库验证该特征的有效性。通过免疫组织化学和定量实时聚合酶链反应（qRT-PCR）检测了真实世界黑色素瘤组织中特征基因的蛋白质和mRNA表达水平。进行功能富集分析和免疫相关分析，以确定该特征的潜在生物学功能和途径。通过连通性图谱（CMAP）预测了10种小分子药物。结果，构建了一个由6个FRGs组成的特征，将黑色素瘤患者分为两个风险组。与低风险组相比，高风险组患者的预后更差，免疫评分更低。免疫相关途径在低风险组中富集。低风险组的免疫功能和免疫细胞浸润明显高于高风险组。证实了这6个FRGs在黑色素瘤和相邻正常组织中的差异表达。此外，在低风险组中观察到免疫检查点分子的表达更高，对免疫治疗的敏感性更高。CMAP数据库中的一些小分子药物具有治疗黑色素瘤的潜力。总体而言，我们鉴定了一种用于黑色素瘤预后预测的新型FRGs特征。基于我们研究中发现的与特征相关的免疫浸润情况，靶向FRGs可能是黑色素瘤的一种治疗选择。
