“刺鸟蛋白（Sonic hedgehog，Shh）-组髓母细胞瘤（medulloblastoma，MB）（Shh-MB）被归类为一种临床和分子上有明显差别的癌症群体，它发源于发育中的神经系统，Shh信号高度异常是其致病的主要驱动因素。我们最近报道RNF220在Shh-MB发展过程中需要维持高水平Shh信号传导，然而，高水平RNF220表达在Shh-MB中的实现机制尚不清楚。在这项研究中，我们发现泛素E3连接酶Smurf1和Smurf2与RNF220相互作用，并对其进行多泛素化和降解。在MB细胞中，Smurf1或Smurf2的敲除或过表达分别通过调控RNF220蛋白水平从而调节Shh信号，促进或抑制细胞增殖、集落形成和异种移植生长。此外，在临床人类MB样本中，Smurf1或Smurf2蛋白水平与RNF220或Shh-MB标志物GAB1的蛋白水平呈负相关。总体而言，该研究突出了Smurf1和Smurf2-RNF220轴在Shh-MB发病机制中的重要性，并为Shh-MB治疗提供了新的治疗靶点。”

Sonic hedgehog (Shh)-group medulloblastoma (MB) (Shh-MB) encompasses a clinically and molecularly distinct group of cancers originating from the developing nervous system with aberrant high Shh signaling as a causative driver. We recently reported that RNF220 is required for sustained high Shh signaling during Shh-MB progression; however, how high RNF220 expression is achieved in Shh-MB is still unclear. In this study, we found that the ubiquitin E3 ligases Smurf1 and Smurf2 interact with RNF220, and target it for polyubiquitination and degradation. In MB cells, knockdown or overexpression of Smurf1 or Smurf2 promotes or inhibits cell proliferation, colony formation and xenograft growth, respectively, by controlling RNF220 protein levels, and thus modulating Shh signaling. Furthermore, in clinical human MB samples, the protein levels of Smurf1 or Smurf2 were negatively correlated with those of RNF220 or GAB1, a Shh-MB marker. Overall, this study highlights the importance of the Smurf1- and Smurf2-RNF220 axes during the pathogenesis of Shh-MB and provides new therapeutic targets for Shh-MB treatment.© 2023. The Author(s).