Neuro-oncology Research Group, Department of Neurosurgery, Cancer Center Amsterdam, VU University Medical Center, Amsterdam, The Netherlands.
Clin Cancer Res. 2012 Aug 1;18(15):4048-58. doi: 10.1158/1078-0432.CCR-12-0399. Epub 2012 Jun 13.
Medulloblastoma is the most common malignant brain tumor in children. Despite recent improvements, the molecular mechanisms driving medulloblastoma are not fully understood and further elucidation could provide cues to improve outcome prediction and therapeutic approaches.
Here, we conducted a meta-analysis of mouse and human medulloblastoma gene expression data sets, to identify potential medulloblastoma tumor suppressor genes.
We identified DAB2IP, a member of the RAS-GTPase-activating protein family (RAS GAP), and showed that DAB2IP expression is repressed in medulloblastoma by EZH2-induced trimethylation. Moreover, we observed that reduced DAB2IP expression correlates significantly with a poor overall survival of patients with medulloblastoma, independent of metastatic stage. Finally, we showed that ectopic DAB2IP expression enhances stress-induced apoptosis in medulloblastoma cells and that reduced expression of DAB2IP in medulloblastoma cells conveys resistance to irradiation-induced cell death.
These results suggest that repression of DAB2IP may at least partly protect medulloblastoma cells from apoptotic cell death. Moreover, DAB2IP may represent a molecular marker to distinguish patients with medulloblastoma at high risk from those with a longer survival prognosis.
髓母细胞瘤是儿童中最常见的恶性脑肿瘤。尽管最近有所改善，但驱动髓母细胞瘤的分子机制仍不完全清楚，进一步阐明这些机制可能为改善预后预测和治疗方法提供线索。
在这里，我们对小鼠和人类髓母细胞瘤基因表达数据集进行了荟萃分析，以鉴定潜在的髓母细胞瘤肿瘤抑制基因。
我们鉴定了 DAB2IP，一种 RAS-GTPase 激活蛋白家族（RAS GAP）的成员，并表明 EZH2 诱导的三甲基化抑制了髓母细胞瘤中的 DAB2IP 表达。此外，我们观察到 DAB2IP 表达减少与髓母细胞瘤患者的总体生存率显著相关，与转移阶段无关。最后，我们表明，异位 DAB2IP 表达增强了髓母细胞瘤细胞对应激诱导的细胞凋亡的反应，而 DAB2IP 在髓母细胞瘤细胞中的表达减少导致对辐射诱导的细胞死亡产生抗性。
这些结果表明，DAB2IP 的抑制至少部分保护了髓母细胞瘤细胞免受凋亡性细胞死亡。此外，DAB2IP 可能代表一种分子标志物，可区分高风险的髓母细胞瘤患者和具有更长生存预后的患者。
