Jin Chen, Li Minhong, Ouyang Yian, Tan Zhigang, Jiang Yugang
Department of Neurosurgery, The Second Xiangya Hospital of Central South University, 139 Renming Road, Changsha, 410011, Hunan, People's Republic of China.
J Neurooncol. 2017 Jun;133(2):247-255. doi: 10.1007/s11060-017-2438-4. Epub 2017 May 15.
Glioma is one of the most lethal malignancies, and increasing reports revealed that microRNAs (miRNAs), a class of small non-coding RNAs, play a critical role in the development and pathology of human gliomas. MiR-424 has been found to be dysregulated in many different types of human cancers. However, the clinical significance and function of miR-424 in glioma remains unclear. Here, based on RTq-PCR analysis in 148 clinical specimens, we found miR-424 expression was significantly decreased in glioma tumor tissues than in adjacent non-neoplastic brain tissues, and decreased miR-424 expression was associated with glioma KPS (P = 0.009) and high grades (P = 0.029). In vitro cellular function assays further revealed that miR-424 inhibited cell invasion and migration, and promoted cell apoptosis. In addition, based on DNA methylation analysis on clinical specimens and cell lines, we found miR-424 promoter CpG island was frequently methylated and correlated with glioma high grades (P = 0.035) and IDH mutation status (P = 0.042). Moreover, the promoter CpG island was demethylated by 5-aza-2'-deoxycytidine treatment in a time-dependent manner and the expression levels of miR-424 were gradually induced and increased. Taken together, our data suggest that the promoter region CpG island methylation is associated with tumor suppressive miR-424 silencing and the pathology of human gliomas.
胶质瘤是最致命的恶性肿瘤之一，越来越多的报告显示，微小RNA（miRNA），一类小的非编码RNA，在人类胶质瘤的发生发展和病理过程中起关键作用。已发现miR-424在许多不同类型的人类癌症中表达失调。然而，miR-424在胶质瘤中的临床意义和功能仍不清楚。在此，基于对148份临床标本的RTq-PCR分析，我们发现胶质瘤肿瘤组织中miR-424的表达明显低于相邻的非肿瘤性脑组织，且miR-424表达降低与胶质瘤患者的KPS评分（P = 0.009）和高分级（P = 0.029）相关。体外细胞功能试验进一步表明，miR-424抑制细胞侵袭和迁移，并促进细胞凋亡。此外，基于对临床标本和细胞系的DNA甲基化分析，我们发现miR-424启动子CpG岛经常发生甲基化，且与胶质瘤高分级（P = 0.035）和异柠檬酸脱氢酶（IDH）突变状态（P = 0.042）相关。而且，用5-氮杂-2'-脱氧胞苷处理后，启动子CpG岛以时间依赖性方式去甲基化，miR-424的表达水平逐渐诱导并增加。综上所述，我们的数据表明启动子区域CpG岛甲基化与肿瘤抑制性miR-424沉默及人类胶质瘤的病理过程相关。
