Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma.
Epigenetic silencing of miRNA-9 is associated with HES1 oncogenic activity and poor prognosis of medulloblastoma.
复制标题
DOI：
10.1038/bjc.2013.764
复制
发表时间：
2014-02-04
影响因子：
8.8
通讯作者：
Grotzer, M. A.
中科院分区：
文献类型：
--
作者：
Fiaschetti, G.;Abela, L.;Nonoguchi, N.;Dubuc, A. M.;Remke, M.;Boro, A.;Grunder, E.;Siler, U.;Ohgaki, H.;Taylor, M. D.;Baumgartner, M.;Shalaby, T.;Grotzer, M. A.
microRNA-9是脑恶性肿瘤（包括髓母细胞瘤）中神经元发育异常表达的关键调控因子。microRNA-9参与成神经管细胞瘤发病的机制尚不清楚，调控这一过程的因素也未被描述。分析了microRNA-9在成神经管细胞瘤细胞系和原代样品中的表达和甲基化状态。我们评估了microRNA-9表达与髓母细胞瘤患者临床预后的关系，并在髓母细胞瘤细胞中功能性验证了microRNA-9修复的影响。与正常胎儿小脑相比，大部分MB样本中的microRNA-9表达受到抑制。低microRNA-9表达与不利的组织病理学变异的诊断和不良的临床结果显著相关。microRNA-9沉默通过癌症特异性CpG岛超甲基化发生。HES1被确定为microRNA-9在成神经管细胞瘤中的直接靶点，microRNA-9的修复被证明可以触发细胞周期阻滞，抑制克隆生长，促进成神经管细胞瘤细胞分化。microRNA-9是一种甲基化沉默的肿瘤抑制因子，可能是髓母细胞瘤预后不良的潜在候选预测标志物。microRNA-9的缺失可能赋予肿瘤细胞增殖优势，并可能与疾病发病机制有关。因此，microRNA-9的重新表达可能是一种新的髓母细胞瘤表观遗传调控策略。
microRNA-9 is a key regulator of neuronal development aberrantly expressed in brain malignancies, including medulloblastoma. The mechanisms by which microRNA-9 contributes to medulloblastoma pathogenesis remain unclear, and factors that regulate this process have not been delineated. Expression and methylation status of microRNA-9 in medulloblastoma cell lines and primary samples were analysed. The association of microRNA-9 expression with medulloblastoma patients' clinical outcome was assessed, and the impact of microRNA-9 restoration was functionally validated in medulloblastoma cells. microRNA-9 expression is repressed in a large subset of MB samples compared with normal fetal cerebellum. Low microRNA-9 expression correlates significantly with the diagnosis of unfavourable histopathological variants and with poor clinical outcome. microRNA-9 silencing occurs via cancer-specific CpG island hypermethylation. HES1 was identified as a direct target of microRNA-9 in medulloblastoma, and restoration of microRNA-9 was shown to trigger cell cycle arrest, to inhibit clonal growth and to promote medulloblastoma cell differentiation. microRNA-9 is a methylation-silenced tumour suppressor that could be a potential candidate predictive marker for poor prognosis of medulloblastoma. Loss of microRNA-9 may confer a proliferative advantage to tumour cells, and it could possibly contribute to disease pathogenesis. Thus, re-expression of microRNA-9 may constitute a novel epigenetic regulation strategy against medulloblastoma.
登录
查看更多内容
DOI：
10.1007/978-1-61779-612-8_8
发表时间：
2012-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Dubuc, Adrian M;Mack, Stephen;Taylor, Michael D
通讯作者：
Taylor, Michael D
影响因子：
8
作者：
Hildebrandt, M. A. T.;Gu, J.;Wu, X.
通讯作者：
Wu, X.
影响因子：
5.1
作者：
Hummel, Richard;Maurer, Jessica;Haier, Joerg
通讯作者：
Haier, Joerg
影响因子：
23.9
作者：
Delaloy C;Liu L;Lee JA;Su H;Shen F;Yang GY;Young WL;Ivey KN;Gao FB
通讯作者：
Gao FB
影响因子：
14.9
作者：
Betel D;Wilson M;Gabow A;Marks DS;Sander C
通讯作者：
Sander C