研究动态
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APOBEC3C 是低级别胶质瘤免疫治疗的新靶点。

APOBEC3C is a novel target for the immune treatment of lower-grade gliomas.

发表日期:2023 Nov 26
作者: Shufa Zhao, Yuntao Li, Jie Xu, Liang Shen
来源: Cell Death & Disease

摘要:

载脂蛋白 B mRNA 编辑催化多肽样 (APOBEC) 3C 型 (A3C) 在过去十年已被确定为癌症分子生物标志物。然而,A3C 在低级别胶质瘤 (LGG) 中改善临床结果的实际作用仍不清楚。本研究旨在探讨A3C在LGGs免疫治疗中的功能。从UCSC Xena中提取RNA测序(RNA-seq)和相应的临床数据,并在中国胶质瘤基因组图谱(CGGA)中验证结果。采用加权基因共表达网络分析(WGCNA)筛选A3C相关基因。进行全面的生物信息分析,评估多水平的表达、存活率和生物学功能,以探讨 A3C 的功能。A3C 在 LGG 中的表达显着高于正常组织,但低于胶质母细胞瘤(GBM),表明其在LGG 的独立预后预测因子。通过 WGCNA 进行无监督聚类分析,发现了 28 个 A3C 相关基因,并确定了具有不同结果和免疫细胞浸润的三种修饰模式。 A3C和A3C评分还与免疫细胞浸润和免疫检查点的表达相关。此外,A3C 评分与化疗敏感性增加相关。单细胞 RNA (scRNA) 分析表明,A3C 最有可能在免疫细胞上表达,如 T 细胞、B 细胞和巨噬细胞。A3C 是 LGG 中免疫相关的预后生物标志物。开发阻断A3C的药物可以提高免疫治疗的效率并提高疾病的生存率。 缩写:A3C:载脂蛋白B mRNA编辑催化多肽样(APOBEC)3C型; LGGs:低级别神经胶质瘤; CGGA:中国胶质瘤基因组图谱; WGCNA:加权基因共表达网络分析; scRNA:单细胞RNA; HGG:高级神经胶质瘤; OS:总生存期; TME:肿瘤微环境; KM:卡普兰-迈耶; PFI:无进展间期; IDH:异柠檬酸脱氢酶; ROC:接收器工作特性; GS:基因显着性; MM:模块成员资格; TIMER:肿瘤免疫估计资源; GSVA:基因集变异分析; ssGSEA:单样本基因集富集分析; PCA:主成分分析; AUC:ROC曲线下面积; HAVCR2:甲型肝炎病毒细胞受体2; PDCD1:程序性细胞死亡1; PDCD1LG2:PDCD1配体2; PTPRC:C型蛋白酪氨酸磷酸酶受体; ACC:肾上腺皮质癌; BLCA:膀胱尿路上皮癌;BRCA:乳腺浸润性癌; CESC:宫颈鳞状细胞癌和宫颈内膜腺癌; CHOL胆管癌; COAD结肠腺癌; DLBC:淋巴肿瘤弥漫性大 B 细胞淋巴瘤; ESCA:食管癌; GBM:多形性胶质母细胞瘤; HNSC:头颈鳞状细胞癌; KICH:肾嫌色症; KIRC:肾透明细胞癌; KIRP:肾肾乳头状细胞癌; LAML:急性髓系白血病; LGG:脑低级别胶质瘤; LIHC:肝细胞癌; LUAD:肺腺癌; LUSC:肺鳞状细胞癌; MESO:间皮瘤; OV:卵巢浆液性囊腺癌; PAAD:胰腺腺癌; PCPG:嗜铬细胞瘤和副神经节瘤; PRAD:前列腺腺癌;阅读:直肠腺癌; SARC:肉瘤; SKCM:皮肤黑色素瘤; STAD:胃腺癌; TGCT:睾丸生殖细胞肿瘤; THCA:甲状腺癌;胸腺瘤:胸腺瘤; UCEC:子宫体子宫内膜癌; UCS:子宫癌肉瘤; UVM:葡萄膜黑色素瘤。
Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) type 3C (A3C) has been identified as a cancer molecular biomarker in the past decade. However, the practical role of A3C in lower-grade gliomas (LGGs) in improving the clinical outcome remains unclear. This study aims to discuss the function of A3C in immunotherapy in LGGs.The RNA-Sequencing (RNA-seq) and corresponding clinical data were extracted from UCSC Xena and the results were verified in the Chinese Glioma Genome Atlas (CGGA). Weighted gene co-expression network analysis (WGCNA) was used for screening A3C-related genes. Comprehensive bioinformation analyses were performed and multiple levels of expression, survival rate, and biological functions were assessed to explore the functions of A3C.A3C expression was significantly higher in LGGs than in normal tissues but lower than in glioblastoma (GBM), indicating its role as an independent prognosis predictor for LGGs. Twenty-eight A3C-related genes were found with WGCNA for unsupervised clustering analysis and three modification patterns with different outcomes and immune cell infiltration were identified. A3C and the A3C score were also correlated with immune cell infiltration and the expression of immune checkpoints. In addition, the A3C score was correlated with increased sensitivity to chemotherapy. Single-cell RNA (scRNA) analysis indicated that A3C most probably expresses on immune cells, such as T cells, B cells and macrophage.A3C is an immune-related prognostic biomarker in LGGs. Developing drugs to block A3C could enhance the efficiency of immunotherapy and improve disease survival.Abbreviation: A3C: Apolipoprotein B mRNA editing catalytic polypeptide-like (APOBEC) type 3C; LGGs: lower-grade gliomas; CGGA: Chinese Glioma Genome Atlas; WGCNA: Weighted gene co-expression network analysis; scRNA: Single-cell RNA; HGG: higher-grade glioma; OS: overall survival; TME: tumor microenvironment; KM: Kaplan-Meier; PFI: progression-free interval; IDH: isocitrate dehydrogenase; ROC: receiver operating characteristic; GS: gene significance; MM: module membership; TIMER: Tumor IMmune Estimation Resource; GSVA: gene set variation analysis; ssGSEA: single-sample gene-set enrichment analysis; PCA: principal component analysis; AUC: area under ROC curve; HAVCR2: hepatitis A virus cellular receptor 2; PDCD1: programmed cell death 1; PDCD1LG2: PDCD1 ligand 2; PTPRC: protein tyrosine phosphatase receptor type C; ACC: Adrenocortical carcinoma; BLCA: Bladder Urothelial Carcinoma;BRCA: Breast invasive carcinoma; CESC: Cervical squamous cell carcinoma and endocervical adenocarcinoma; CHOLCholangiocarcinoma; COADColon adenocarcinoma; DLBC: Lymphoid Neoplasm Diffuse Large B-cell Lymphoma; ESCA: Esophageal carcinoma; GBM: Glioblastoma multiforme; HNSC: Head and Neck squamous cell carcinoma; KICH: Kidney Chromophobe; KIRC: Kidney renal clear cell carcinoma; KIRP: Kidney renal papillary cell carcinoma; LAML: Acute Myeloid Leukemia; LGG: Brain Lower Grade Glioma; LIHC: Liver hepatocellular carcinoma; LUAD: Lung adenocarcinoma; LUSC: Lung squamous cell carcinoma; MESO: Mesothelioma; OV: Ovarian serous cystadenocarcinoma; PAAD: Pancreatic adenocarcinoma; PCPG: Pheochromocytoma and Paraganglioma; PRAD: Prostate adenocarcinoma; READ: Rectum adenocarcinoma; SARC: Sarcoma; SKCM: Skin Cutaneous Melanoma; STAD: Stomach adenocarcinoma; TGCT: Testicular Germ Cell Tumors; THCA: Thyroid carcinoma; THYM: Thymoma; UCEC: Uterine Corpus Endometrial Carcinoma; UCS: Uterine Carcinosarcoma; UVM: Uveal Melanoma.