A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer

作者：Bu Pengcheng^*; Wang Lihua; Chen Kai Yuan; Srinivasan Tara; Murthy Preetish Kadur Lakshminarasimha; Tung Kuei Ling; Varanko Anastasia Kristine; Chen Huanhuan Joyce; Ai Yiwei; King Sarah; Lipkin Steven M; Shen Xiling^*

来源：Cell Stem Cell, 2016, 18(2): 189-202.

DOI：10.1016/j.stem.2016.01.006

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.

• 出版日期2016-2-4