Antagonistic modulation of gliomagenesis by Pax6 and Olig2 in PDGF-induced oligodendroglioma
Antagonistic modulation of gliomagenesis by Pax6 and Olig2 in PDGF-induced oligodendroglioma
复制标题
DOI：
10.1002/ijc.27606
复制
发表时间：
2012-10-01
影响因子：
6.4
通讯作者：
Malatesta, Paolo
中科院分区：
文献类型：
--
作者：
Appolloni, Irene;Calzolari, Filippo;Malatesta, Paolo
胶质瘤是中枢神经系统的侵袭性肿瘤，起源于增殖的神经细胞。因此，神经干细胞或祖细胞生物学的调节因子可能影响脑肿瘤发生的各个方面，如维持肿瘤增殖潜能。我们研究了Pax6在pdgf - b驱动的少突胶质细胞瘤体内模型中的作用，Pax6是一种神经源性转录因子，已经被认为是人类胶质瘤的阳性预后标志物。在该系统中，Pax6的表达通过诱导肿瘤起始细胞增殖减少和获得分化特性，严重损害肿瘤的增殖。Pax6的过表达与Olig2的下调相关，Olig2是一种bHLH转录因子，通常在成人神经源性生态位中拮抗Pax6，并在神经干和祖细胞的维持中起关键作用。此外，我们发现Olig2对于维持少突胶质细胞的恶性是严格需要的，因为通过干扰RNA使其沉默可以消除肿瘤的增殖。我们最终证明，这种功能至少部分取决于ID4的沉默，ID4是一种显性的bHLH负蛋白，其上调发生在Olig2缺失之后。在我们的模型中，ID4的上调模拟了Olig2的缺失，从而损害胶质瘤细胞的肿瘤增殖潜能。因此，我们的数据建立了神经干细胞生物学生理调节因子在调节神经胶质肿瘤恶性肿瘤中的相关性，并在此背景下为它们的功能相互作用提供了支持。
Gliomas are aggressive tumors of the central nervous system originating from proliferating neural cells. Regulators of neural stem or progenitor cells biology may thus influence aspects of brain tumorigenesis, such as the maintenance of tumor-propagating potential. We investigated the role of Pax6, a neurogenic transcription factor already suggested as a positive prognostic marker for human gliomas, in a well-characterized in vivo model of PDGF-B-driven oligodendroglioma. In this system, the expression of Pax6 severely impairs tumor propagation by inducing a reduction of cell proliferation and the acquisition of differentiation traits in tumor-initiating cells. The overexpression of Pax6 correlates with a downregulation of Olig2, a bHLH transcription factor that normally antagonizes Pax6 in adult neurogenic niches and that plays a key role in the maintenance of neural stem and progenitor cells. Furthermore, we found that Olig2 is strictly required to maintain the malignancy of oligodendroglioma cells, since its silencing by interfering RNA abrogates tumor propagation. We finally show evidence that this function depends, at least in part, on the silencing of ID4, a dominant negative bHLH protein, whose upregulation follows Olig2 loss. In our model, the upregulation of ID4 mimics the loss of Olig2 in impairing the tumor-propagating potential of glioma cells. Our data, therefore, establish the relevance of physiological regulators of neural stem cell biology in regulating glial tumor malignancy and provide support for their functional interactions in this context.