Department of Medical Biochemistry and Microbiology, Science for Life Laboratory, Box 582, Biomedical Center, Uppsala University, SE-75123, Uppsala, Sweden.
Ludwig Cancer Research, Science for Life Laboratory, Box 595, Biomedical Center, Uppsala University, SE-75124, Uppsala, Sweden.
Oncogene. 2018 May;37(19):2515-2531. doi: 10.1038/s41388-018-0136-0. Epub 2018 Feb 16.
Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor β (TGFβ) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGFβ1 signaling activity. Exogenous TGFβ1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGFβ pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.
多形性胶质母细胞瘤是一种脑恶性肿瘤，其特征为高度异质性、侵袭性和对现有治疗方法的耐药性，这些特性与胶质瘤干细胞（GSCs）的发生有关。转化生长因子β（TGFβ）促进自我更新，骨形态发生蛋白（BMP）诱导 GSCs 分化。BMP7 诱导转录因子 Snail 促进 GSCs 中的星形胶质细胞分化，并在体内抑制肿瘤生长。我们证明 Snail 抑制 GSCs 的干性。Snail 与 SMAD 信号转导介质相互作用，产生 BMP 信号的正反馈回路，并转录抑制 TGFB1 基因，降低 TGFβ1 信号活性。外源性 TGFβ1 在体外拮抗 Snail 的功能，体内促进 Nestin 的增殖和重新表达，证实了 Snail 对 TGFB1 基因抑制的重要性。总之，新的研究结果突出了 Snail 如何差异调节对立的 BMP 和 TGFβ 途径的活性，从而促进星形胶质细胞命运转换并抑制 GSCs 的干性。
