铁死亡调控基因亚精胺/精胺N1-乙酰基转移酶1在脑胶质瘤中的 表达及临床意义
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国家自然科学基金项目(81802483,81902528);北京市医院管理中心青年人才培养“青 苗”计划(QML20190507)


Expression of ferroptosis regulatory genen SAT1 in brain gliomas and its clinical significance
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    目的 探讨铁死亡调控基因亚精胺/ 精胺N1- 乙酰基转移酶1(SAT1)在脑胶质瘤患者中的 表达趋势及临床意义。方法 纳入中国脑胶质瘤基因组图谱计划(CGGA,http://www.cgga.org.cn/)及美 国癌症基因组图谱计划(TCGA, http://www.cancergenome.nih.gov/)数据库中3 批次共1 720 例(CGGA-325 组、CGGA-693 组及TCGA组分别为325、693、702 例)脑胶质瘤患者的临床资料及其胶质瘤组织样本表 达谱数据,分析SAT1 基因的表达趋势及与患者病理、分子病理指标、预后等因素的相关关系。应用细 胞模型研究SAT1 基因在脑胶质瘤中的生物学功能。采用Kaplan-Meier生存曲线比较SAT1 基因表达量 不同的脑胶质瘤患者的生存差异;应用受试者工作特征(ROC)曲线评估SAT1 对脑胶质瘤患者1 年和 3 年总生存率的预测作用。结果 在脑胶质瘤患者样本中,SAT1 在异柠檬酸脱氢酶(IDH)野生型胶质 母细胞瘤中表达水平最高,在IDH突变联合1p19q 缺失的低级别胶质瘤中表达水平最低(CGGA-325 组、 CGGA-693 组及TCGA 组患者中,均P< 0.001)。在世界卫生组织(WHO)Ⅲ级及Ⅳ级的患者中,SAT1 高 表达的患者预后更差(不同数据库、不同级别SAT1 高表达及低表达患者的中位生存期分别为:CGGA- 325 组WHO Ⅲ级患者,485 d 和1 321 d,P< 0.05;CGGA-325 组WHO Ⅳ级患者, 286 d 和493 d,P< 0.05; CGGA-693 组WHO Ⅲ级患者, 836 d 和2 982 d,P< 0.05;CGGA-693 组WHO Ⅳ级患者,356 d 和459 d, P< 0.05;TCGA 组WHO Ⅲ级患者, 31.57 个月和114 个月,P< 0.05;TCGA 组WHO Ⅳ级患者, 11.24 个 月和13.77 个月,P < 0.05)。CGGA-325 组患者中,应用ROC 曲线评估SAT1 对患者1 年和3 年生存的预 测能力,其曲线下面积(AUC)分别为0.725、0.793;在CGGA-693 组数据中,其AUC 分别为0.615、0.671; 在TCGA 组中,其AUC 分别为0.791、0.808(均P< 0.001);在细胞模型中,下调SAT1基因表达,可抑制胶 质瘤细胞增殖率(两种细胞系作用24 h 及48 h 后, 均P< 0.05)。结论 SAT1基因与脑胶质瘤患者级别、 分子亚型、预后等显著相关,可能通过激活肿瘤细胞增殖发挥作用。

    Abstract:

    Objective To investigate the expression pattern and clinical significance of spermidine/ spermine N1-acetyltransferase 1( SAT1), ferroptosis regulatory genen, in brain gliomas. Methods The clinical data and expression profile of glioma tissue samples in a total of 3 batches of 1 720 patients were obtained from CGGA and TCGA database. There were 325, 693 and 702 cases in CGGA-325 group, CGGA- 693 group and TCGA group, respectively. The expression trend of SAT1 gene and its correlation with pathology,molecular pathology and prognosis were analyzed. Vitro assays was used to study the biological function of SAT1 gene in glioma. Kaplan-Meier survival curve was used to compare the survival differences of glioma patients with different SAT1 gene expression. Receiver operating characteristic( ROC) curve was used to evaluate the predictive effect of SAT1 on 1-year and 3-year overall survival of patients with glioma. Results In glioma tissue samples, SAT1 showed highest expression in IDH wildtype glioblastomas and lowest expression in IDH mutant and 1p19q codeleted lower grade gliomas( P<0.001 in all 3 groups). In WHO grade Ⅲ and Ⅳ giomas, patients with high expression of SAT1 showed more unfavorable prognosis( the median survival time of patients with high and low SAT1 expression in different databases and grades was as below: CGGA-325 group, WHO grade Ⅲ patients, 485 days and 1 321 days, P< 0.05; CGGA-325 group, WHO grade Ⅳ patients, 286 days and 493 days, P < 0.05; CGGA-693 group, WHO grade Ⅲ patients, 836 days and 2982 days, P < 0.05; CGGA-693 group, WHO grade Ⅳ patients, 356 days and 459 days, P< 0.05; TCGA group, WHO grade Ⅲ patients, 31.57 months and 114 months, P< 0.05; TCGA group, WHO grade Ⅳ patients, 11.24 months and 13.77 months, P< 0.05). The area under the curve( AUC) of SAT1 on 1-year and 3-year overall survival in CGGA-325 group was 0.725 and 0.793, respectively, 0.615 and 0.671 in CGGA-693 group, 0.791 and 0.808 in TCGA group,( P<0.001). In vitro assays showed that down-regulation of SAT1 in glioma cells could inhibit cell proliferation( P<0.05 after 24 hours and 48 hours of the treatment). Conclusions SAT1 was associated with glioma grade, molecular subtypes and patients' prognosis, which might due to the proliferation promotion effects.

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张传宝 刘汉杰 王志亮 王政 王洪军.铁死亡调控基因亚精胺/精胺N1-乙酰基转移酶1在脑胶质瘤中的 表达及临床意义[J].神经疾病与精神卫生,2021,21(5):
DOI :10.3969/j. issn.1009-6574.2021.05.005.

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  • 在线发布日期: 2021-06-02