Pyroptosis relates to tumor microenvironment remodeling and prognosis: A pan-cancer perspective.
Pyroptosis relates to tumor microenvironment remodeling and prognosis: A pan-cancer perspective.
复制标题
细胞焦亡与肿瘤微环境重塑和预后相关：泛癌视角
DOI：
10.3389/fimmu.2022.1062225
复制
发表时间：
2022
影响因子：
7.3
通讯作者：
Yuan, Yawei
中科院分区：
文献类型：
--
作者：
Khan, Muhammad;Ai, Meiling;Du, Kunpeng;Song, Jingjing;Wang, Baiyao;Lin, Jie;Ren, Anbang;Chen, Chengcong;Huang, Zhong;Qiu, Wenze;Zhang, Jiangyu;Tian, Yunhong;Yuan, Yawei
焦亡是一种与炎症和疾病有关的程序性细胞死亡的炎症形式。此外，诱导细胞焦亡因其释放抗癌免疫反应的能力而被认为是抗癌疗法。利用癌症基因组图谱 (TCGA) 中的可用数据，系统地分析了泛癌中焦亡相关基因 (PRG) 的表达、基因组畸变和临床意义。获得 GSVA 评分来评估焦亡水平并将癌症分为低焦亡和高焦亡组。使用免疫组织化学 (IHC) 评估选定肿瘤类型（COAD、HNSC、KIRC、LIHC、LUAD、LUSC）中主要 PRG（GSDMC、GSDMD、GSDME、NLRP3、NLRC4、IL1B）的差异表达。免疫组织化学 (IHC) 肿瘤的选择基于其在 TCGA 癌症中的表达模式、临床相关性、肿瘤流行病学和样本可用性。 PRGs的差异表达在各种癌症中很明显，并且与由基因组变异和表观遗传异常驱动的预后相关，例如单核苷酸变异（SNV）、拷贝数变异（CNV）和DNA甲基化水平。例如，低级别胶质瘤 (LGG)、葡萄膜黑色素瘤 (UVM) 和肾肾透明细胞癌 (KIRC) 中 PRG 的甲基化可预测生存率的提高，因为 PRG 的上调在这些癌症中存在风险。焦亡水平在 15 种癌症中显着区分肿瘤与正常样本，随癌症分期呈进展趋势，观察到癌症亚型之间的差异，并与癌症预后显着相关。根据 Kaplan-Meier 生存曲线估计，较高的焦亡水平与大多数癌症的 OS（KIRC、LGG 和 UVM）、PFS（GBM、KIRC、LGG、PRAD、THCA 和 THYM）和 DSS（KIRC 和 LGG）的最差预后相关。此外，焦亡水平强烈表明存在大量 CD8+ T 细胞和其他 T 细胞亚型的热肿瘤免疫微环境。多种致癌途径，如 P53 途径、DNA 修复、KRAS 信号传导、上皮间质转化 (EMT)、IL6 JAK STAT3 信号传导、IL2 STAT5 信号传导、PI3K AKTMTOR 信号传导和血管生成，在癌症的细胞焦亡 hi 亚组中丰富。 PRG 的遗传改变极大地影响细胞焦亡水平和癌症预后。无论癌症预后如何，相对较热的肿瘤免疫微环境都与细胞焦亡相关。总的来说，我们的研究揭示了焦亡在癌症中的关键作用，并强调了基于焦亡的治疗漏洞。
Pyroptosis is an inflammatory form of programmed cell death implicated in inflammation and disease. Moreover, inducing pyroptosis has been appreciated as anti-cancer therapy for its ability to unleash anti-cancer immune responses. Utilizing the data available in The Cancer Genome Atlas (TCGA), pyroptosis-related genes’ (PRGs) expression, genomic aberrations, and clinical significance were systematically analyzed in pan-cancer. A GSVA score was obtained to rate pyroptosis level and divide the cancers into pyroptosis-low and pyroptosis-high groups. Immunohistochemistry (IHC) was used to evaluate the differential expression of major PRGs (GSDMC, GSDMD, GSDME, NLRP3, NLRC4, IL1B) in selected tumor types (COAD, HNSC, KIRC, LIHC, LUAD, LUSC). Selection of tumors for immunohistochemistry (IHC) was based on their expression pattern in TCGA cancers, clinical relevance, tumor epidemiology, and sample availability. Differential expression of PRGs was evident in various cancers and associated with prognosis which was driven by genomic variations and epigenetic abnormalities, such as single nucleotide variations (SNVs), copy number variation (CNV) and DNA methylation level. For example, methylation of PRGs in lower grade glioma (LGG), uveal melanoma (UVM) and kidney renal clear cell carcinoma (KIRC) were predictive of improved survival as upregulation of PRGs was risky in these cancers. Pyroptosis level significantly differentiated tumor from normal samples in 15 types of cancers, exhibited a progressive trend with cancer stage, observed variation among cancer subtypes, and showed a significant association with cancer prognosis. Higher pyroptosis level was associated with worst prognosis in majority of the cancers in terms of OS (KIRC, LGG, and UVM), PFS (GBM, KIRC, LGG, PRAD, THCA, and THYM) and DSS (KIRC and LGG) as estimated by Kaplan-Meier survival curves. Moreover, Pyroptosis level was strongly indicative of a hot tumor immune microenvironment with high presence of CD8+ T cell and other T cell subtypes. Several oncogenic pathways, such as P53 pathway, DNA repair, KRAS signaling, epithelial-mesenchymal transition (EMT), IL6 JAK STAT3 signaling, IL2 STAT5 signaling, PI3K AKT MTOR signaling and angiogenesis, were enriched in pyroptosis-hi subgroups across cancers. Genetic alterations in PRGs greatly influence the pyroptosis level and cancer prognosis. A relatively hot tumor immune microenvironment was associated with pyroptosis irrespective of the cancer prognosis. Overall, our study reveals the critical role of pyroptosis in cancer and highlights pyroptosis-based therapeutic vulnerabilities.
登录
查看更多内容
DOI：
10.1038/s41573-021-00154-z
发表时间：
2021-05
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Liu X;Xia S;Zhang Z;Wu H;Lieberman J
通讯作者：
Lieberman J
影响因子：
5.7
作者：
Akino, Kimishige;Toyota, Minoru;Tokino, Takashi
通讯作者：
Tokino, Takashi
影响因子：
4.5
作者：
Carl-Mcgrath, Stacy;Schneider-Stock, Regine;Roecken, Christoph
通讯作者：
Roecken, Christoph
DOI：
10.1073/pnas.1016814108
发表时间：
2010-12-14
影响因子：
11.1
作者：
Hu, Bo;Elinav, Eran;Flavell, Richard A.
通讯作者：
Flavell, Richard A.
上皮-间质转化诱导 GSDME 转录激活以治疗炎症性焦亡
影响因子：
5.5
作者：
Jia C;Zhang Z;Tang J;Cai MC;Zang J;Shi K;Sun Y;Wu J;Shi H;Shi W;Ma P;Zhao X;Yu Z;Fu Y;Zhuang G
通讯作者：
Zhuang G