背景:Ferroptosis是一种铁依赖性类型的调节性细胞死亡,并与肺腺癌(LUAD)有关。有证据证明了谷氨酸-半胱氨酸连接酶催化亚基(GCLC)在铁凋亡中的关键作用,但其在LUAD中的作用尚不清楚。在这里,我们探讨了GCLC和相关基因在LUAD预后和免疫中的意义以及潜在的分子机制。
方法:这项工作收集了mRNA,miRNA,DNA甲基化,来自TCGA-LUAD的体细胞突变和拷贝数变异数据。WGCNA用于选择GCLC相关基因,通过单和多变量cox回归分析建立GCLC相关预后特征.通过BERSORT估计免疫成分,和两个免疫治疗队列的实体瘤进行了分析。最后评估了多组学调控机制。
结果:我们的结果显示GCLC在LUAD中过度表达,并可能导致不良生存。生成了一个预后模型,在预测方面拥有准确和独立的表现。GCLC,相关基因与免疫成分和免疫检查点显著相关。高GCLC表达与对抗PD-L1和抗CTLA-4治疗的更好反应相关。推断了它们可能的DNA甲基化位点,例如,cg19740353中的低甲基化可能有助于GCLC上调。频繁的基因突变也影响了它们的表达。上游转录因子(E2F1/3/4等。),miRNA的转录后调控(hsa-mir-30c-1等。),lncRNAs(C8orf34-AS1等.),并鉴定了IGF2BP1介导的m6A修饰。还发现NOP58介导的SUMO化翻译后修饰。
结论:一起,我们表明GCLC和相关基因在LUAD的预后和免疫中起着至关重要的作用,它们的表达可以通过复杂的多组学机制来控制。
BACKGROUND: Ferroptosis is an iron-dependent type of regulated cell death, and has been implicated in lung adenocarcinoma (LUAD). Evidence has proved the key role of glutamate-cysteine ligase catalytic subunit (
GCLC) in ferroptosis, but its role in LUAD remains unclear. Herein, we explored the implications of
GCLC and relevant genes in LUAD prognosis and immunity as well as underlying molecular mechanisms.
METHODS: This work gathered mRNA, miRNA, DNA methylation, somatic mutation and copy-number variation data from TCGA-LUAD. WGCNA was utilized for selecting
GCLC-relevant genes, and a
GCLC-relevant prognostic signature was built by uni- and multivariate-cox regression analyses. Immune compositions were estimated via CIBERSORT, and two immunotherapy cohorts of solid tumors were analyzed. Multi-omics regulatory mechanisms were finally assessed.
RESULTS: Our results showed that GCLC was overexpressed in LUAD, and potentially resulted in undesirable survival. A prognostic model was generated, which owned accurate and independent performance in prognostication.
GCLC, and relevant genes were notably connected with immune compositions and immune checkpoints. High
GCLC expression was linked with better responses to anti-PD-L1 and anti-CTLA-4 treatment. Their possible DNA methylation sites were inferred, e.g., hypomethylation in cg19740353 might contribute to GCLC up-regulation. Frequent genetic mutations also affected their expression. Upstream transcription factors (E2F1/3/4, etc.), post-transcriptional regulation of miRNAs (hsa-mir-30c-1, etc.), lncRNAs (C8orf34-AS1, etc.), and IGF2BP1-mediated m6A modification were identified. It was also found NOP58-mediated SUMOylation post-translational modification.
CONCLUSIONS: Together, we show that GCLC and relevant genes exert crucial roles in LUAD prognosis and immunity, and their expression can be controlled by complex multi-omics mechanisms.