Department of Pathology, Kitasato University School of Medicine, Kanagawa, Japan.
Lab Invest. 2012 Apr;92(4):511-21. doi: 10.1038/labinvest.2011.196. Epub 2012 Jan 9.
Sox factors function as either activators or repressors of β-catenin/TCF transcription depending on the cellular context and associated interacting proteins. Our previous study provided evidence that alteration in β-catenin signaling is an essential event during transdifferentiation toward the morular phenotype of endometrial carcinomas (Em Cas). Here, we focused on related functional roles of Sox factors. Of eight Sox factors investigated, Sox4 could enhance β-catenin/TCF4 transcription, through upregulation of TCF4 at the transcription level, without any direct β-catenin association. Cells stably overexpressing Sox4 showed significant decreases in proliferation rate, along with increases in expression of p21(WAF1), as well as TCF4, in contrast to increased cell growth observed with knockdown. Of these factors, only Sox7 could transcriptionally upregulate Sox4 expression, but it also resulted in not only inhibition of Sox4-meditated activation of β-catenin/TCF4-driven transcription, but also repression of its own promoter activity, indicating the existence of very complex feedback loop for Sox-mediated signal cascades. Finally, Sox4 immunoreactivity was frequently pronounced in morular lesions of Em Cas, the expression being positively correlated with status of β-catenin, TCF4, and Sox7, and inversely with cell proliferation. These data therefore suggest that Sox4 may serve as a positive regulator of β-catenin signaling through alteration in TCF4 expression during morular differentiation of Em Ca cells, leading to inhibition of cell proliferation. In addition, Sox7 may also participate in the process, having complex roles in modulation of signaling.
Sox 因子可根据细胞环境和相关相互作用蛋白的不同，作为 β-连环蛋白/TCF 转录的激活剂或抑制剂。我们之前的研究提供了证据，表明β-连环蛋白信号的改变是子宫内膜癌（Em Cas）向桑葚体表型分化过程中的一个重要事件。在这里，我们关注 Sox 因子的相关功能作用。在我们研究的八个 Sox 因子中，Sox4 可以通过转录水平上 TCF4 的上调来增强 β-连环蛋白/TCF4 转录，而无需与 β-连环蛋白直接结合。稳定过表达 Sox4 的细胞增殖率显著下降，同时 p21(WAF1)和 TCF4 的表达增加，而敲低则观察到细胞生长增加。在这些因子中，只有 Sox7 可以转录上调 Sox4 的表达，但这不仅导致 Sox4 介导的β-连环蛋白/TCF4 驱动转录激活的抑制，还导致其自身启动子活性的抑制，表明 Sox 介导的信号级联存在非常复杂的反馈回路。最后，Sox4 免疫反应性在 Em Cas 的桑葚体病变中经常明显，其表达与β-连环蛋白、TCF4 和 Sox7 的状态呈正相关，与细胞增殖呈负相关。因此，这些数据表明 Sox4 可能通过改变 Em Ca 细胞桑葚体分化过程中 TCF4 的表达，作为 β-连环蛋白信号的正调节剂，从而抑制细胞增殖。此外，Sox7 也可能参与该过程，在信号调节中具有复杂的作用。
