Bmi-1 is essential for the tumorigenicity of neuroblastoma cells
Bmi-1 is essential for the tumorigenicity of neuroblastoma cells
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Bmi-1 对于神经母细胞瘤细胞的致瘤性至关重要
DOI：
10.2353/ajpath.2007.060754
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发表时间：
2007-04-01
影响因子：
6
通讯作者：
Ding, Han-Fei
中科院分区：
文献类型：
--
作者：
Cui, Hongjuan;Hu, Bo;Ding, Han-Fei
癌基因的激活是大多数人类癌症发病的基础。在神经母细胞瘤中，癌基因MYCN的扩增发生在22%的病例中，与疾病的晚期和预后不良有关。识别神经母细胞瘤中持续突变或过度表达的其他癌基因，对于从分子水平理解其发病过程至关重要。在这里，我们报告了癌基因BMI-1在人类神经母细胞瘤中高度表达。细胞系和原发肿瘤。在人类疾病的动物模型MYCN转基因小鼠中，神经母细胞瘤的发展与BMI-1表达水平的显著增加有关。Bmi-1通过抑制MYCN的凋亡活性，与MYCN协同转化良性S型神经母细胞瘤细胞和禽神经嵴细胞。重要的是，BMI-1的下调削弱了神经母细胞瘤细胞在软琼脂中生长的能力，并在免疫缺陷小鼠中诱导肿瘤。此外，BMI-1基因敲除的神经母细胞瘤异种移植的特征是雪旺氏基质的数量显著增加，这是与临床上有利的神经母细胞瘤相关的组织学特征。这些发现表明BMI-1在神经母细胞瘤的发病机制中起着关键作用，并为神经母细胞瘤异质性的分子基础提供了洞察力。
Activation of oncogenes underlies the pathogenesis of most human cancers. In neuroblastoma, amplification of the oncogene MYCN occurs in similar to 22% of cases and is associated with advanced stages of the disease and poor prognosis. identification of other oncogenes that are consistently mutated or overexpressed in neuroblastoma is crucial for a molecular understanding of the pathogenic process. Here, we report that the oncogene Bmi-1 is highly expressed in human neuroblastoma. cell lines and primary tumors. Neuroblastoma development in MYCN transgenic mice, an animal model for the human disease, was associated with a marked increase in the levels of Bmi-1 expression. Bmi-1 cooperated with MYCN in transformation of benign S-type neuroblastoma cells and avian neural crest cells by inhibiting the apoptotic activity of MYCN. importantly, down-regulation of Bmi-1 impaired the ability of neuroblastoma cells to grow in soft agar and induce tumors in immunodeficient mice. Moreover, Bmi-1-knockdown neuroblastoma xenografts were characterized by a significant increase in the amount of Schwannian stroma, a histological feature associated with clinically favorable neuroblastomas. These findings suggest a crucial role for Bmi-1 in neuroblastoma pathogenesis and provide insights into the molecular basis of neuroblastoma heterogeneity.