Center of Medical Genetics, University of Antwerp and Antwerp University Hospital, Antwerp, Belgium.
Molecular Signaling and Cell Death Unit, VIB Center for Inflammation Research, VIB, Ghent, Belgium.
Int J Cancer. 2021 Jun 15;148(12):2872-2883. doi: 10.1002/ijc.33390. Epub 2020 Dec 8.
Gasdermin E (GSDME), a gene originally involved in hereditary hearing loss, has been associated with several types of cancer in the last two decades. Recently, GSDME was identified as a pore-forming molecule, which is activated following caspase-3-mediated cleavage resulting in so-called secondary necrosis following apoptotic cell death, or in primary necrotic cell death without an apoptotic phase, so-called pyroptosis-like. This implication in cell death execution suggests its potential role as a tumor suppressor. GSDME also exhibited a cancer type-specific differential methylation pattern between tumor tissues and normal cells, implying GSDME gene methylation as both a pan-cancer and cancer type-specific detection biomarker. A bit paradoxically, GSDME protein expression is considered to be less suited as biomarker, and although its ablation does not protect the cell against eventual cell death, its protein expression might still operate in tumor immunogenicity due to its capacity to induce (secondary) necrotic cell death, which has enhanced immunogenic properties. Additionally, GSDME gene expression has been shown to be associated with favorable prognosis following chemotherapy, and it could therefore be a potential predictive biomarker. We provide an overview of the different associations between GSDME gene methylation, gene expression and tumorigenesis, and explore their potential use in the clinic. Our review only focuses on GSDME and summarizes the current knowledge and most recent advances on GSDME's role in cancer formation, its potential as a biomarker in cancer and on its promising role in immunotherapies and antitumor immune response.
Gasdermin E (GSDME)，最初与遗传性听力损失有关的基因，在过去二十年中与多种类型的癌症有关。最近，GSDME 被鉴定为一种形成孔的分子，它在 caspase-3 介导的切割后被激活，导致凋亡细胞死亡后的所谓继发性坏死，或没有凋亡阶段的所谓类细胞焦亡性坏死。这种在细胞死亡执行中的作用暗示其作为肿瘤抑制因子的潜在作用。GSDME 还在肿瘤组织和正常细胞之间表现出癌症类型特异性的差异甲基化模式，暗示 GSDME 基因甲基化作为泛癌和癌症类型特异性检测生物标志物。有点矛盾的是，GSDME 蛋白表达被认为不太适合作为生物标志物，尽管其缺失不能保护细胞免受最终的细胞死亡，但由于其诱导（继发性）坏死细胞死亡的能力，其蛋白表达仍可能在肿瘤免疫原性中起作用，因为它具有增强的免疫原性。此外，已经表明 GSDME 基因表达与化疗后的有利预后相关，因此它可能是一种潜在的预测生物标志物。我们提供了 GSDME 基因甲基化、基因表达与肿瘤发生之间的不同关联的概述，并探讨了它们在临床中的潜在用途。我们的综述仅关注 GSDME，并总结了 GSDME 在癌症形成中的作用、作为癌症生物标志物的潜力以及在免疫治疗和抗肿瘤免疫反应中的有前途的作用的最新知识和最新进展。
