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目的探讨脑胶质瘤组织中PER1、PER2、CRY1、CRY2、CLOCK、BMAL1和NPAS2时钟基因启动子区甲基化状态与脑胶质瘤发生、发展的关系。方法采用甲基化特异性PCR检测脑胶质瘤组织及其癌旁正常组织(对照)PER1、CRY1、CRY2、CLOCK、BMAL1、NPAS2等时钟基因启动子区甲基化状态。结果脑胶质瘤组织与癌旁正常组织中PER1、CLOCK时钟基因启动子区均未有甲基化;脑胶质瘤组织中NPAS2、PER2时钟基因启动子区甲基化频率明显高于癌旁正常组织(均P<0.05);两种组织中CRY1、CRY2和BMAL1时钟基因启动子区甲基化频率比较,差异均无统计学意义(均P>0.05)。不同级别脑胶质瘤组织中PER1、CLOCK时钟基因启动子区均未有甲基化;高级别脑胶质瘤(Ⅲ~Ⅳ级)组织中NPAS2时钟基因启动子区甲基化频率高于低级别胶质瘤(Ⅰ~Ⅱ级)组织(P<0.05);不同级别脑胶质瘤组织中CRY1、CRY2、BMAL1和PER2时钟基因启动子区甲基化频率比较,差异均无统计学意义(均P>0.05)。结论 NPAS2、PER2时钟基因启动子区甲基化频率明显增高;NPAS2时钟基因启动子区甲基化频率越高,脑胶质瘤的恶性程度越高。NPAS2、PER2时钟基因启动子区DNA甲基化修饰可能是脑胶质瘤发生、发展的重要机制。
Objective To investigate the relationship between the methylation status of PER1, PER2, CRY1, CRY2, CLOCK, BMAL1 and NPAS2 promoter genes and the occurrence and development of glioma in glioma tissues. Methods Methylation-specific PCR was used to detect the methylation status of PER1, CRY1, CRY2, CLOCK, BMAL1, NPAS2 and other clock genes in glioma tissues and adjacent normal tissues (control). Results There was no methylation in the promoter regions of PER1 and CLOCK clock genes in glioma tissues and adjacent normal tissues. The frequencies of promoter methylation of NPAS2 and PER2 genes in glioma tissues were significantly higher than those in adjacent tissues (P <0.05). There was no significant difference in methylation frequency of promoter region between CRY1, CRY2 and BMAL1 in both tissues (all P> 0.05). There was no methylation in PER1 and CLOCK clock genes in different grades of glioma tissues. The methylation frequency of NPAS2 clock gene promoter in high grade gliomas (Ⅲ ~ Ⅳ grade) was higher than that in low grade gliomas (P <0.05). There was no significant difference in methylation frequencies of CRY1, CRY2, BMAL1 and PER2 promoter among different grades of glioma All P> 0.05). Conclusions The frequency of methylation of NPAS2 and PER2 clock gene promoter regions was significantly increased. The higher the methylation frequency of NPAS2 clock gene promoter region, the higher the malignant degree of glioma. DNA methylation modification of NPAS2 and PER2 promoter may play an important role in the development and progression of glioma.