Identification and validation of roles of lysyl oxidases in the predictions of prognosis, chemotherapy and immunotherapy in glioma.
Identification and validation of roles of lysyl oxidases in the predictions of prognosis, chemotherapy and immunotherapy in glioma.
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赖氨酰氧化酶在神经胶质瘤预后、化疗和免疫治疗预测中的作用的鉴定和验证
DOI：
10.3389/fphar.2022.990461
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发表时间：
2022
影响因子：
5.6
通讯作者：
中科院分区：
文献类型：
--
作者：
背景：先前的研究表明赖氨酰氧化酶家族酶（LOX）是肿瘤进展和重塑免疫微环境的促成因素。然而，关于LOXs在神经胶质瘤这种高侵袭性脑肿瘤的预后预测、化疗和免疫治疗中的综合分析却很少。我们目前的工作旨在通过生物信息学分析和实验验证，探讨胶质瘤中不同LOXs表达的预后价值、化疗药物敏感性和免疫治疗。 方法：我们从公共数据库收集了基因表达数据和临床特征，包括中国胶质瘤基因组图谱（CGGA）-325、CGGA-693、癌症基因组图谱（TCGA）、IMvigor210和Van Allen 2015队列。分析临床病理因素与LOXs表达差异的相关性。采用ROC曲线和Kaplan-Meier分析评价预后预测能力。使用 pRRophetic 软件包通过不同的 LOX 表达水平预测化疗药物敏感性。还通过 R 软件中的多种算法分析了免疫评分、免疫细胞浸润和免疫检查点表达水平。最后，分别通过实时定量 PCR 和蛋白质印迹验证了神经胶质瘤细胞（T98G 和 A172）中 LOX 的 mRNA 和蛋白表达。 结果：我们的结果表明，高水平的 LOX 表达与神经胶质瘤分级、年龄较大和 MGMT 非甲基化状态呈正相关，而 LOX 的升高与 IDH 突变或 1p/19q 共缺失呈负相关。此外，LOX水平较低的胶质瘤患者也表现出更好的预后。此外，不同的 LOX 表达与至少 12 种化疗药物敏感性相关。此外，还发现LOXs高表达的胶质瘤患者表现出更高的免疫细胞浸润富集分数和免疫检查点水平增加，这表明不同的LOXs表达水平对于胶质瘤免疫治疗的关键作用。 LOXs 表达在肿瘤免疫治疗中的预测作用也在 IMvigor 210 和 Van Allen 2015 两个免疫治疗队列中得到了验证。实验结果表明，LOX、LOXL1、LOXL2 和 LOXL3 在胶质瘤细胞系中的 mRNA 和蛋白水平表达较高。 结论：我们的研究结果表明 LOX 对神经胶质瘤患者的预后、化疗和免疫治疗具有有效的预测价值。
Background: Previous investigations have illustrated that lysyl oxidase family enzymes (LOXs) are contributing factors for tumor progression and remodeling immunomicroenvironment. However, it is scarce regarding comprehensive analysis of LOXs in the predictions of prognosis, chemotherapy and immunotherapy in glioma, the highly invasive brain tumor. Our present work aimed to explore the prognostic value, chemotherapeutic drug sensitivity and immunotherapy according to distinct LOXs expressions in glioma through bioinformatics analysis and experimental verification. Methods: We collected gene expression data and clinical characteristics from the public databases including Chinese Glioma Genome Atlas (CGGA)-325, CGGA-693, the Cancer Genome Atlas (TCGA), IMvigor210 and Van Allen 2015 cohorts. The correlations between the clinicopathological factors and differential LOXs expressions were analyzed. The ROC curve and Kaplan-Meier analysis were conducted to evaluate the prediction ability of prognosis. Chemotherapeutic drug sensitivity via distinct LOXs expression levels was predicted using the pRRophetic package. Immune score, immune cell infiltration and immune checkpoint expression levels were also analyzed through diverse algorithms in R software. Finally, mRNA and protein expressions of LOXs were validated in glioma cells (T98G and A172) by real-time quantitative PCR and Western blot, respectively. Results: Our results demonstrated that high levels of LOXs expressions were positively associated with glioma grades, older age and MGMT unmethylated status while elevations of LOXs were negatively correlated with IDH mutation or 1p/19q co-deletion. Furthermore, the glioma patients with low levels of LOXs also exhibited better prognosis. Also, differential LOXs expressions were associated with at least 12 chemotherapeutic drug sensitivity. Besides, it was also found that glioma patients with high LOXs expressions showed higher enrichment scores for immune cell infiltration and increased levels of immune checkpoints, suggesting the critical role of distinct LOXs expression levels for glioma immunotherapy. The predictive roles of LOXs expression in tumor immunotherapy were also validated in two immunotherapy cohorts including IMvigor 210 and Van Allen 2015. Experimental results revealed that expressions of LOX, LOXL1, LOXL2, and LOXL3 were higher in glioma cell lines at mRNA and protein levels. Conclusion: Our findings altogether indicate that LOXs have potent predictive value for prognosis, chemotherapy and immunotherapy in glioma patients.
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影响因子：
8.5
作者：
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影响因子：
11.2
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影响因子：
4.3
作者：
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