Department of Gastroenterology and Hepatology, Kyoto University Graduate School of Medicine, Kyoto 606-8501, Japan.
Development. 2012 Mar;139(6):1071-82. doi: 10.1242/dev.069070. Epub 2012 Feb 8.
Notch signaling regulates intestinal development, homeostasis and tumorigenesis, but its precise downstream mechanism remains largely unknown. Here we found that inactivation of the Notch effectors Hes1, Hes3 and Hes5, but not Hes1 alone, led to reduced cell proliferation, increased secretory cell formation and altered intestinal structures in adult mice. However, in Apc mutation-induced intestinal tumors, inactivation of Hes1 alone was sufficient for reducing tumor cell proliferation and inducing differentiation of tumor cells into all types of intestinal epithelial cells, but without affecting the homeostasis of normal crypts owing to genetic redundancy. These results indicated that Hes genes cooperatively regulate intestinal development and homeostasis and raised the possibility that Hes1 is a promising target to induce the differentiation of tumor cells.
Notch 信号通路调节肠道发育、稳态和肿瘤发生，但确切的下游机制仍知之甚少。本研究发现，Notch 效应物 Hes1、Hes3 和 Hes5 的失活，但单独失活 Hes1 不会导致成年小鼠的细胞增殖减少、分泌细胞形成增加和肠道结构改变。然而，在 Apc 突变诱导的肠道肿瘤中，单独失活 Hes1 足以减少肿瘤细胞增殖并诱导肿瘤细胞向所有类型的肠上皮细胞分化，但由于遗传冗余，不会影响正常隐窝的稳态。这些结果表明 Hes 基因协同调节肠道发育和稳态，并提出 Hes1 可能是诱导肿瘤细胞分化的有前途的靶点。
