Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells
Maternal embryonic leucine zipper kinase is a key regulator of the proliferation of malignant brain tumors, including brain tumor stem cells
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DOI：
10.1002/jnr.21471
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发表时间：
2008-01-01
影响因子：
4.2
通讯作者：
Kornblum, Harley I.
中科院分区：
文献类型：
--
作者：
Nakano, Ichiro;Masterman-Smith, Michael;Kornblum, Harley I.
新出现的证据表明，神经干细胞和脑肿瘤通过类似的途径调节其增殖。在之前的一项研究中，我们证明了母体胚胎亮氨酸拉链激酶（Melk）在小鼠神经干细胞中高度表达并调节其增殖。在这里，我们描述了MELK表达如何与脑肿瘤的病理分级相关，其表达水平与较短的生存期显著相关，特别是在年轻的胶质母细胞瘤患者中。在正常人星形胶质细胞中，MELK仅微弱表达，MELK敲除不会显著影响其生长，而Ras和Akt过表达的星形胶质细胞具有上调的MELK表达，MELK敲除的效果在这些转化的星形胶质细胞中更突出。在来自人胶质母细胞瘤和髓母细胞瘤的原代培养物中，通过siRNA敲低MELK导致这些肿瘤的增殖和存活的抑制。此外，我们表明MELK siRNA显着抑制增殖，并在一定程度上，在体外从胶质母细胞瘤分离的干细胞的存活。这些结果证明了MELK在脑肿瘤（包括其干细胞）增殖中的关键作用，并表明MELK可能是治疗高级别脑肿瘤的引人注目的分子靶点。(c)2007 Wiley-Liss，Inc.
Emerging evidence suggests that neural stem cells and brain tumors regulate their proliferation via similar pathways. In a previous study, we demonstrated that maternal embryonic leucine zipper kinase (Melk) is highly expressed in murine neural stem cells and regulates their proliferation. Here we describe how MELK expression is correlated with pathologic grade of brain tumors, and its expression levels are significantly correlated with shorter survival, particularly in younger glioblastoma patients. In normal human astrocytes, MELK is only faintly expressed, and MELK knockdown does not significantly influence their growth, whereas Ras and Akt overexpressing astrocytes have up-regulated MELK expression, and the effect of MELK knockdown is more prominent in these transformed astrocytes. In primary cultures from human glioblastoma and medulloblastoma, MELK knockdown by siRNA results in inhibition of the proliferation and survival of these tumors. Furthermore, we show that MELK siRNA dramatically inhibits proliferation and, to some extent, survival of stem cells isolated from glioblastoma in vitro. These results demonstrate a critical role for MELK in the, proliferation of brain tumors, including their stem cells, and suggest that MELK may be a compelling molecular target for treatment of high-grade braintumors. (c) 2007 Wiley-Liss, Inc.