从一个新的 pyroptosis 相关风险特征贡献 TMZ 抵抗、预后和 GBM 的免疫浸润。
Contributes to TMZ Resistance, Prognosis, and Immune Infiltration in GBM from a Novel Pyroptosis-Associated Risk Signature.
机构信息
Department of Head and Neck Surgery, Hunan Cancer Hospital, Xiangya School of Medicine, Central South University, Changsha, 410013 Hunan, China.
School of Medicine, Hunan Normal University, Changsha, 410013 Hunan, China.
出版信息
Dis Markers. 2022 Apr 1;2022:4534080. doi: 10.1155/2022/4534080. eCollection 2022.
BACKGROUND
Pyroptosis is a form of programmed cell death, playing a significant role in cancer. Glioblastoma multiforme (GBM) is the most common malignant brain tumor. The poor prognosis in GBM due to temozolomide (TMZ) resistance has been widely discussed. Such being the case, the correlation between TMZ resistance and pyroptosis is seldom investigated. On this basis, this paper aims to explore the potential prognostic value of genes related to TMZ resistance and pyroptosis as well as their relationship to the immune microenvironment in GBM.
METHODS
A total of 103 patients from TCGA were assigned to a training cohort; 190 from CGGA were assigned to a validation cohort. The prognostic risk model reflecting pyroptosis and TMZ resistance was built from the training cohort using multivariate Cox regression and performed validation. RT-qPCR was used to examine the expression of 4 genes from the risk signature. was selected for overexpression and verified using the western blot. The TMZ IC50 of -overexpressed cell lines was determined by CCK8.
RESULTS
A four genes-based risk signature was established and validated, separating GBM patients into high- and low-risk groups. Compared with the low-risk group, the high-risk group presented worse clinical survival outcomes. Its differential expressed genes were enriched in immune-related pathways and closely related to the immune microenvironment. Moreover, RT-qPCR results suggested that , , and were significantly upregulated in TMZ-resistant strains, while was downregulated. overexpressed GBM cell lines had higher TMZ IC50, implying an increased resistance of TMZ.
CONCLUSION
A novel gene signature relevant to pyroptosis and TMZ resistance was constructed and could be used for the prognosis of GBM. The four genes from the risk model might play a potential role in antitumor immunity and serve as therapeutic targets for GBM.
背景
细胞焦亡是一种程序性细胞死亡方式，在癌症中发挥着重要作用。多形性胶质母细胞瘤（GBM）是最常见的恶性脑肿瘤。替莫唑胺（TMZ）耐药导致的 GBM 预后不良已被广泛讨论。在这种情况下，TMZ 耐药与细胞焦亡之间的相关性很少被研究。基于此，本文旨在探讨与 TMZ 耐药和细胞焦亡相关的基因的潜在预后价值及其与 GBM 免疫微环境的关系。
方法
从 TCGA 中选取 103 例患者作为训练队列，从 CGGA 中选取 190 例患者作为验证队列。使用多变量 Cox 回归从训练队列中构建反映细胞焦亡和 TMZ 耐药的预后风险模型，并进行验证。使用 RT-qPCR 检测风险特征中 4 个基因的表达情况。选择 进行过表达，并通过 Western blot 进行验证。使用 CCK8 测定 -过表达细胞系的 TMZ IC50。
结果
建立并验证了一个基于 4 个基因的风险模型，将 GBM 患者分为高风险和低风险组。与低风险组相比，高风险组的临床生存结局更差。其差异表达基因富集在免疫相关通路中，与免疫微环境密切相关。此外，RT-qPCR 结果表明，TMZ 耐药株中 、 、 和 表达显著上调，而 表达下调。过表达 GBM 细胞系的 TMZ IC50 更高，表明 TMZ 耐药性增加。
结论
构建了一个与细胞焦亡和 TMZ 耐药相关的新基因特征，可以用于 GBM 的预后。风险模型中的 4 个基因可能在抗肿瘤免疫中发挥潜在作用，可作为 GBM 的治疗靶点。
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