Lian Zhen, Liu Xue, Li Xue
Department of Emergency, Tianjin Medical University Cancer Institute & Hospital, National Clinical Research Center for Cancer, Tianjin's Clinical Research Center for Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, 300060, China.
Department of Comprehensive Treatment Ward, Mudan People's Hospital of Heze, Heze, 274000, China.
BMC Cancer. 2025 Jan 2;25(1):5. doi: 10.1186/s12885-024-13379-z.
cGAS plays an important role in regulating both tumor immune responses and DNA damage repair. Nevertheless, there was little research that comprehensively analyzed the correlation between cGAS and the tumor microenvironment, immune cell infiltration, and DNA damage repair in different cancers. In this study, The Cancer Genome Atlas (TCGA) and Cancer Cell Line Encyclopedia (CCLE) data were used to analyze the mRNA expression and genomic alterations of cGAS in pan-cancer. The HPA database was used to explore the protein levels of cGAS in normal tissues and cancers. Correlation analysis were performed to explore the role of cGAS in interferon expression, immune cell infiltrations, DNA damage repair, and predictive immune markers. The prognostic value of cGAS was analyzed using survival data from the TCGA, Kaplan-Meier plotter database, and PrognoScan database. Lastly, the role of cGAS in DNA damage repair signaling and interferon signaling was validated in NSCLC cell lines. The results showed that cGAS was widely expressed in human normal tissues and various cancers, and the expression of cGAS was significantly upregulated in almost all of the solid cancers. Genomic analysis indicated that the expression of cGAS was positively correlated with copy number levels, while negatively correlated with the methylation levels of cGAS promoter. In addition, the level of cGAS was positively correlated with type I interferons expression, infiltration levels of most immune cell types, TMB and MSI levels, stromal and immune scores, and DNA damage repair gene sets including nonhomologous end joining and homologous recombination pathway. Survival analysis indicated that cGAS levels were associated with patient prognosis in several cancers. Lastly, in vitro study showed knockdown of cGAS expression inhibits the DNA damage repair signaling pathway and interferon signaling in NSCLC. In conclusions, cGAS is wildly activated in human cancers, which might participate in regulating cancer immunity and DNA damage repair. cGAS could be used as an effective target for cancer treatment and might be a potential predictive immune marker.
环鸟苷酸-腺苷酸合成酶（cGAS）在调节肿瘤免疫反应和DNA损伤修复中均发挥着重要作用。然而，鲜有研究全面分析cGAS与不同癌症中的肿瘤微环境、免疫细胞浸润及DNA损伤修复之间的相关性。在本研究中，利用癌症基因组图谱（TCGA）和癌细胞系百科全书（CCLE）数据，分析了cGAS在泛癌中的mRNA表达及基因组改变。利用人类蛋白质图谱（HPA）数据库探究正常组织和癌症中cGAS的蛋白水平。进行相关性分析以探究cGAS在干扰素表达、免疫细胞浸润、DNA损伤修复及预测性免疫标志物中的作用。使用来自TCGA、Kaplan-Meier绘图仪数据库和PrognoScan数据库的生存数据，分析cGAS的预后价值。最后，在非小细胞肺癌（NSCLC）细胞系中验证了cGAS在DNA损伤修复信号通路和干扰素信号通路中的作用。结果显示，cGAS在人类正常组织和多种癌症中广泛表达，且在几乎所有实体癌中cGAS的表达均显著上调。基因组分析表明，cGAS的表达与拷贝数水平呈正相关，而与cGAS启动子的甲基化水平呈负相关。此外，cGAS水平与I型干扰素表达、大多数免疫细胞类型的浸润水平、肿瘤突变负荷（TMB）和微卫星不稳定性（MSI）水平、基质和免疫评分以及包括非同源末端连接和同源重组途径在内的DNA损伤修复基因集呈正相关。生存分析表明，cGAS水平在几种癌症中与患者预后相关。最后，体外研究表明，敲低cGAS表达可抑制NSCLC中的DNA损伤修复信号通路和干扰素信号通路。总之，cGAS在人类癌症中被广泛激活，可能参与调节癌症免疫和DNA损伤修复。cGAS可作为癌症治疗的有效靶点，可能是一种潜在的预测性免疫标志物。
