Department of Pediatrics, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mol Oncol. 2021 May;15(5):1486-1506. doi: 10.1002/1878-0261.12903. Epub 2021 Feb 7.
Expression of the RE1-silencing transcription factor (REST), a master regulator of neurogenesis, is elevated in medulloblastoma (MB) tumors. A cell-intrinsic function for REST in MB tumorigenesis is known. However, a role for REST in the regulation of MB tumor microenvironment has not been investigated. Here, we implicate REST in remodeling of the MB vasculature and describe underlying mechanisms. Using REST mice, we demonstrate that elevated REST expression in cerebellar granule cell progenitors, the cells of origin of sonic hedgehog (SHH) MBs, increased vascular growth. This was recapitulated in MB xenograft models and validated by transcriptomic analyses of human MB samples. REST upregulation was associated with enhanced secretion of proangiogenic factors. Surprisingly, a REST-dependent increase in the expression of the proangiogenic transcription factor E26 oncogene homolog 1, and its target gene encoding the vascular endothelial growth factor receptor-1, was observed in MB cells, which coincided with their localization at the tumor vasculature. These observations were confirmed by RNA-Seq and microarray analyses of MB cells and SHH-MB tumors. Thus, our data suggest that REST elevation promotes vascular growth by autocrine and paracrine mechanisms.
RE1 沉默转录因子（REST）的表达在髓母细胞瘤（MB）肿瘤中升高，RE1 沉默转录因子是神经发生的主要调节因子。已知 REST 在 MB 肿瘤发生中有细胞内在的功能。然而，REST 在调节 MB 肿瘤微环境中的作用尚未被研究。在这里，我们将 REST 牵连到 MB 血管重塑中，并描述了潜在的机制。使用 REST 小鼠，我们证明了小脑颗粒细胞祖细胞中 REST 表达的升高，即声猬（SHH）MB 的起源细胞，增加了血管生长。这在 MB 异种移植模型中得到了重现，并通过对人类 MB 样本的转录组分析得到了验证。REST 的上调与促血管生成因子的分泌增强有关。令人惊讶的是，在 MB 细胞中观察到了 REST 依赖性的促血管生成转录因子 E26 致癌基因同源物 1 及其编码血管内皮生长因子受体-1 的靶基因的表达增加，这与它们在肿瘤血管中的定位相吻合。这些观察结果通过对 MB 细胞和 SHH-MB 肿瘤的 RNA-Seq 和微阵列分析得到了证实。因此，我们的数据表明，REST 升高通过自分泌和旁分泌机制促进血管生长。
