Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells
Sonic hedgehog regulates Bmi1 in human medulloblastoma brain tumor-initiating cells
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DOI：
10.1038/onc.2011.232
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发表时间：
2012-01-01
期刊：
影响因子：
8
通讯作者：
Singh, S. K.
中科院分区：
文献类型：
--
作者：
Wang, X.;Venugopal, C.;Singh, S. K.
Bmi1是一个关键的干细胞调控基因，涉及许多侵袭性癌症的发病机制，包括髓母细胞瘤。Bmi1的过表达促进细胞增殖，是hedgehog （Hh）通路驱动的肿瘤发生所必需的。本研究旨在确定Sonic hedgehog基因（Shh）是否调控儿童成神经管细胞瘤脑肿瘤起始细胞（BTICs）中关键的干细胞调控基因Bmi1。虽然目前文献提示Shh通路基因与Bmi1表达之间存在相关性，但是否存在直接调控机制尚不清楚。为了研究Shh是否诱导Bmi1的表达，我们用Shh配体和kaad -环巴胺（Shh拮抗剂）处理了髓母细胞瘤细胞系和原代样品的干细胞富集群体。我们的数据表明Bmi1的表达与Shh配体浓度的增加呈正相关。染色质免疫沉淀显示，Gli1优先结合Bmi1启动子，Gli1过表达和下调分别使Bmi1转录物水平升高和降低。体外和体内Bmi1敲低实验表明，Hh信号不仅驱动Bmi1的表达，而且存在一种反馈机制，Bmi1的下游效应物可能反过来激活Hh通路基因。这些发现暗示Bmi1和Hh在成神经管细胞瘤BTIC维持中是相互不可或缺的途径。最近髓母细胞瘤的分子特征也表明，Bmi1在髓母细胞瘤的所有亚群中都过表达，特别是在最具侵袭性的亚型中。最后，尽管最近发现了BTIC标记物，但这些细胞群的分子特征仍不清楚。在这项工作中，我们提出BTIC标记CD133可以分离具有Hh受体表型的细胞群，从而证明CD133+ Hh受体细胞和CD133- Hh分泌细胞之间存在细胞间相互作用。中华肿瘤杂志，2012,31,187-199；doi: 10.1038 / onc.2011.232;2011年6月20日在线发布
Bmi1 is a key stem cell regulatory gene implicated in the pathogenesis of many aggressive cancers, including medulloblastoma. Overexpression of Bmi1 promotes cell proliferation and is required for hedgehog (Hh) pathway-driven tumorigenesis. This study aimed to determine if Sonic hedgehog (Shh) modulates the key stem cell regulatory gene Bmi1 in childhood medulloblastoma brain tumor-initiating cells (BTICs). Although current literature suggests that there is a correlation between Shh pathway genes and Bmi1 expression, it is unclear whether there is indeed a direct regulatory mechanism. To address whether Shh induces expression of Bmi1, stem cell-enriched populations from medulloblastoma cell lines and primary samples were treated with Shh ligand and KAAD-cyclopamine (Shh antagonist). Our data indicate that Bmi1 expression positively correlates with increasing Shh ligand concentrations. Chromatin immunoprecipitation reveals that Gli1 preferentially binds to the Bmi1 promoter, and Bmi1 transcript levels are increased and decreased by Gli1 overexpression and down-regulation, respectively. Knockdown experiments of Bmi1 in vitro and in vivo demonstrate that Hh signaling not only drives Bmi1 expression, but a feedback mechanism exists wherein downstream effectors of Bmi1 may, in turn, activate Hh pathway genes. These findings implicate Bmi1 and Hh as mutually indispensable pathways in medulloblastoma BTIC maintenance. Recent molecular characterization of medulloblastoma also reveals that Bmi1 is overexpressed across all subgroups of medulloblastoma, particularly in the most aggressive subtypes. Lastly, despite recent identification of BTIC markers, the molecular characterization of these cell populations remains unclear. In this work, we propose that the BTIC marker CD133 may segregate a cell population with a Hh-receptor phenotype, thus demonstrating a cell-cell interaction between the CD133+ Hh receptor cells and the CD133- Hh-secreting cells. Oncogene (2012) 31, 187-199; doi:10.1038/onc.2011.232; published online 20 June 2011