Stögbauer Louise, Thomas Christian, Wagner Andrea, Warneke Nils, Bunk Eva Christine, Grauer Oliver, Canisius Julian, Paulus Werner, Stummer Walter, Senner Volker, Brokinkel Benjamin
1Department of Neurosurgery.
2Institute of Neuropathology, and.
J Neurosurg. 2020 Dec 11;135(3):845-854. doi: 10.3171/2020.7.JNS193097. Print 2021 Sep 1.
Chemotherapeutic options for meningiomas refractory to surgery or irradiation are largely unknown. Human telomerase reverse transcriptase (hTERT) promoter methylation with subsequent TERT expression and telomerase activity, key features in oncogenesis, are found in most high-grade meningiomas. Therefore, the authors investigated the impact of the demethylating agent decitabine (5-aza-2'-deoxycytidine) on survival and DNA methylation in meningioma cells.
hTERT promoter methylation, telomerase activity, TERT expression, and cell viability and proliferation were investigated prior to and after incubation with decitabine in two benign (HBL-52 and Ben-Men 1) and one malignant (IOMM-Lee) meningioma cell line. The global effects of decitabine on DNA methylation were additionally explored with DNA methylation profiling.
High levels of TERT expression, telomerase activity, and hTERT promoter methylation were found in IOMM-Lee and Ben-Men 1 but not in HBL-52 cells. Decitabine induced a dose-dependent significant decrease of proliferation and viability after incubation with doses from 1 to 10 μM in IOMM-Lee but not in HBL-52 or Ben-Men 1 cells. However, effects in IOMM-Lee cells were not related to TERT expression, telomerase activity, or hTERT promoter methylation. Genome-wide methylation analyses revealed distinct demethylation of 14 DNA regions after drug administration in the decitabine-sensitive IOMM-Lee but not in the decitabine-resistant HBL-52 cells. Differentially methylated regions covered promoter regions of 11 genes, including several oncogenes and tumor suppressor genes that to the authors' knowledge have not yet been described in meningiomas.
Decitabine decreases proliferation and viability in high-grade but not in benign meningioma cell lines. The effects of decitabine are TERT independent but related to DNA methylation changes of promoters of distinct tumor suppressor genes and oncogenes.
对于手术或放疗难治的脑膜瘤，化疗方案在很大程度上尚不清楚。人端粒酶逆转录酶（hTERT）启动子甲基化以及随后的TERT表达和端粒酶活性是肿瘤发生的关键特征，在大多数高级别脑膜瘤中都有发现。因此，作者研究了去甲基化药物地西他滨（5-氮杂-2'-脱氧胞苷）对脑膜瘤细胞存活和DNA甲基化的影响。
在两种良性（HBL-52和Ben-Men 1）和一种恶性（IOMM-Lee）脑膜瘤细胞系中，用地西他滨孵育前后，研究hTERT启动子甲基化、端粒酶活性、TERT表达以及细胞活力和增殖情况。此外，通过DNA甲基化谱分析进一步探究地西他滨对DNA甲基化的整体影响。
在IOMM-Lee和Ben-Men 1细胞中发现高水平的TERT表达、端粒酶活性和hTERT启动子甲基化，但在HBL-52细胞中未发现。在IOMM-Lee细胞中，用1至10μM剂量的地西他滨孵育后，其增殖和活力呈剂量依赖性显著降低，但在HBL-52或Ben-Men 1细胞中未出现这种情况。然而，IOMM-Lee细胞中的作用与TERT表达、端粒酶活性或hTERT启动子甲基化无关。全基因组甲基化分析显示，在对地西他滨敏感的IOMM-Lee细胞中给药后，14个DNA区域出现明显去甲基化，而在对地西他滨耐药的HBL-52细胞中未出现。差异甲基化区域覆盖了11个基因的启动子区域，包括一些癌基因和肿瘤抑制基因，据作者所知，这些基因在脑膜瘤中尚未被描述。
地西他滨可降低高级别脑膜瘤细胞系的增殖和活力，但对良性脑膜瘤细胞系无效。地西他滨的作用不依赖于TERT，但与不同肿瘤抑制基因和癌基因启动子的DNA甲基化变化有关。
