Preliminary Study on GZMA- and GSDMB-Associated Pyroptosis and CD8+ T Cell-Mediated Immune Evasion in Skin Cutaneous Melanoma.

IF 3.3 4区 医学 Q3 CHEMISTRY, MEDICINAL
Jianqin Chen, Zhirong Huang, Fengfeng Xie, Jing Liu, Wen Sun, Jingli Xu, Wenfang Xie
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引用次数: 0

Abstract

Background: Skin cutaneous melanoma (SKCM) is a life-threatening malignancy, and pyroptosis-mediated inflammatory response is associated with SKCM progression. We aimed to uncover the underlying pathogenesis of SKCM based on pyroptosis features.

Method: The single-cell and bulk RNA-seq data and clinical information of SKCM patients were downloaded from the TCGA and GEO databases, and the REACTOME_ PYROPTOSIS.v2024.1.Hs.gmt from the MSigDB database was used for Gene Set Enrichment Analysis (GSEA). Differentially expressed gene (DEG) analysis was performed utilizing the "limma" R package, and the "GSVA" R package was used for the analysis of pyroptosis pathway activation. In addition, scRNA-seq analysis and cell communication analysis were carried out by employing the "Seurat" R package and "CellChat" R package, respectively. Gene expression was measured using quantitative reverse transcription polymerase chain reaction (qRT-PCR), while cell counting kit-8 (CCK-8), wound healing, and Transwell assays were carried out to assess cell proliferation, migration, and invasion, respectively.

Results: DEGs analysis detected no significant pyroptosis-related DEGs. Analysis of the expression of two representative pyroptosis genes (GZMA and GSDMB) revealed that GZMA was significantly upregulated in the SKCM tissues, but the expression of GSDMB was downregulated. The pyroptosis pathway was not activated in the tumor group. In addition, we observed that high expression of GZMA and GSDMB was closely associated with a favorable outcome in SKCM. The two genes were downregulated in SKCM cells, while the overexpression of GZMA significantly impaired the proliferation, migration, and invasion ability of SKCM cells. Nine main cell subpopulations were identified, and GZMA was specifically overexpressed in CD8+ T cells. Gene function analysis revealed that specific genes of CD8+ T cells were enriched in cell death-related and inflammation activation pathways. Cell communication demonstrated that CD8+ T cells interacted with melanocytes through the CD99-CD99 and HLA-C-KIR2DL3 ligand-receptor pairs.

Conclusion: Based on the pyroptosis features in SKCM, this study found that blocking GZMA proteins in CD8+ T cells within melanocytes may be the underlying pathogenesis for tumor immune escape in cancer.

皮肤黑色素瘤中GZMA-和gsdmb相关的焦亡和CD8+ T细胞介导的免疫逃避的初步研究
背景:皮肤黑色素瘤(SKCM)是一种危及生命的恶性肿瘤,焦热介导的炎症反应与SKCM的进展有关。我们的目的是基于焦亡特征揭示SKCM的潜在发病机制。方法:从TCGA和GEO数据库下载SKCM患者的单细胞和大量RNA-seq数据和临床资料,并下载REACTOME_ pyrotosis .v2024.1. hs。使用MSigDB数据库中的gmt进行基因集富集分析(GSEA)。差异表达基因(DEG)分析使用“limma”R包,“GSVA”R包分析焦亡途径激活。此外,使用“Seurat”R包和“CellChat”R包分别进行scRNA-seq分析和细胞通讯分析。采用定量逆转录聚合酶链反应(qRT-PCR)检测基因表达,采用细胞计数试剂盒-8 (CCK-8)、伤口愈合和Transwell试验分别评估细胞增殖、迁移和侵袭。结果:DEGs分析未检测到明显的与热释热相关的DEGs。对两个具有代表性的焦亡基因GZMA和GSDMB的表达分析显示,GZMA在SKCM组织中显著上调,而GSDMB的表达下调。肿瘤组焦亡通路未被激活。此外,我们观察到GZMA和GSDMB的高表达与SKCM的良好预后密切相关。这两个基因在SKCM细胞中表达下调,而GZMA的过表达显著降低了SKCM细胞的增殖、迁移和侵袭能力。鉴定出9个主要细胞亚群,GZMA在CD8+ T细胞中特异性过表达。基因功能分析显示,CD8+ T细胞在细胞死亡相关通路和炎症激活通路中富集特异性基因。细胞通讯表明,CD8+ T细胞通过CD99-CD99和HLA-C-KIR2DL3配体受体对与黑素细胞相互作用。结论:基于SKCM的焦亡特征,本研究发现阻断黑色素细胞内CD8+ T细胞中的GZMA蛋白可能是肿瘤免疫逃逸的潜在发病机制。
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来源期刊
CiteScore
6.40
自引率
2.90%
发文量
186
审稿时长
3-8 weeks
期刊介绍: Current Topics in Medicinal Chemistry is a forum for the review of areas of keen and topical interest to medicinal chemists and others in the allied disciplines. Each issue is solely devoted to a specific topic, containing six to nine reviews, which provide the reader a comprehensive survey of that area. A Guest Editor who is an expert in the topic under review, will assemble each issue. The scope of Current Topics in Medicinal Chemistry will cover all areas of medicinal chemistry, including current developments in rational drug design, synthetic chemistry, bioorganic chemistry, high-throughput screening, combinatorial chemistry, compound diversity measurements, drug absorption, drug distribution, metabolism, new and emerging drug targets, natural products, pharmacogenomics, and structure-activity relationships. Medicinal chemistry is a rapidly maturing discipline. The study of how structure and function are related is absolutely essential to understanding the molecular basis of life. Current Topics in Medicinal Chemistry aims to contribute to the growth of scientific knowledge and insight, and facilitate the discovery and development of new therapeutic agents to treat debilitating human disorders. The journal is essential for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important advances.
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