A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.
A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.
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DOI：
10.1016/j.stem.2016.01.006
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发表时间：
2016-02-04
期刊：
影响因子：
23.9
通讯作者：
Shen X
中科院分区：
文献类型：
--
作者：
Bu P;Wang L;Chen KY;Srinivasan T;Murthy PK;Tung KL;Varanko AK;Chen HJ;Ai Y;King S;Lipkin SM;Shen X
新出现的证据表明，microRNA可以启动不对称分裂，但microRNA和蛋白质细胞命运决定因素是否相互协调仍不清楚。在这里，我们发现miR-34a直接抑制早期结肠癌干细胞（CCSCs）中的Numb，形成一个靶向Notch的不连贯前馈回路（IFFL），以稳定地分离干细胞和非干细胞命运。IFFL的扰动导致一个新的中间细胞群具有可塑性和模糊的身份。Lgr5+小鼠肠/结肠干细胞（ISCs）主要进行对称分裂，但当促炎反应导致过度增殖时，会开启不对称分裂以抑制ISCs的数量。在这种应激下，miR-34a的缺失抑制了不对称分裂，加剧了Lgr5+ ISC的增殖。总的来说，我们的数据表明，microRNA和蛋白质细胞命运决定因素协同增强细胞命运决定的稳健性，它们提供了一种保护机制，防止炎症或致癌突变诱导的干细胞增殖。
Emerging evidence suggests that microRNAs can initiate asymmetric division, but whether microRNA and protein cell fate determinants coordinate with each other remains unclear. Here we show that miR-34a directly suppresses Numb in early-stage colon cancer stem cells (CCSCs), forming an incoherent feedforward loop (IFFL) targeting Notch to separate stem and non-stem cell fates robustly. Perturbation of the IFFL leads to a new intermediate cell population with plastic and ambiguous identity. Lgr5+ mouse intestinal/colon stem cells (ISCs) predominantly undergo symmetric division, but turn on asymmetric division to curb the number of ISCs when proinflammatory response causes excessive proliferation. Deletion of miR-34a inhibits asymmetric division and exacerbates Lgr5+ ISC proliferation under such stress. Collectively, our data indicate that microRNA and protein cell fate determinants coordinate to enhance robustness of cell fate decision, and they provide a safeguard mechanism against stem cell proliferation induced by inflammation or oncogenic mutation.