Crosstalk between Wnt and Notch signaling in colonic epithelium.

已知Wnt和Notch通路共同调节肠上皮的增殖和分化；然而，它们功能相互作用的分子机制尚不清楚。在这项研究中，我们旨在研究这两种途径在结肠上皮中的信号串扰。首先，通过使用几种人类结肠癌来源的细胞系，我们证明了Hath1（一种已知参与Notch信号传导的bHLH转录因子）的表达受到蛋白酶体介导的蛋白质降解的调节，而蛋白酶体介导的蛋白质降解受Wnt信号传导的控制。我们还发现，Wnt/Notch信号对Hath1的翻译后调控对于结肠细胞的命运决定很重要。其次，为了研究Wnt/Notch信号之间的串扰，我们建立了一种体外分离培养正常结肠上皮的新方法。通过这种方法，结肠细胞持续生长，Lgr5+结肠干细胞由于Wnt/Notch激活而优先扩增。我们还首次发现，培养的结肠细胞在移植后能够再生受损的受体小鼠上皮。这些数据将为进一步阐明Wnt/Notch信号相互作用调控结肠上皮细胞再生特性和/或恶性转化的分子机制奠定基础。

Wnt and Notch pathways are known to function together to regulate proliferation and differentiation of intestinal epithelium ; however, the molecular mechanism of their functional interplay remains unclear. In this study, we aimed at investigating the signaling crosstalk between these two pathways in colonic epithelium. First, by using several human colon cancer-derived cell lines, we have demonstrated that the expression of Hath1, a bHLH transcription factor known to be involved in Notch signaling, is regulated by the proteasome-mediated protein degradation that is under the control of Wnt signaling. We also showed that this post-translational regulation of Hath1 by Wnt/Notch signals is important for cell fate determination of colonic cells. Second, in order to investigate the crosstalk between Wnt/Notch signals, we have established a novel method to isolate and culture normal colonic epithelium in vitro. By this method, colonic cells continuously grow and the Lgr5+colonic stem cells preferentially expand as a result of Wnt/Notch activation. We also showed for the first time that the cultured colonic cells are able to regenerate damaged epithelium in recipient mice when transplanted. These data would built a basis for the future study to elucidate molecular mechanism that govern the interplay of Wnt/Notch signals to regulate the regenerative properties and/or malignant transformation of colonic epithelial cells.