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

TitleA miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.
Publication TypeJournal Article
Year of Publication2016
AuthorsBu, P, Wang, L, Chen, K-Y, Srinivasan, T, Murthy, PKadur Laks, Tung, K-L, Varanko, AKristine, Chen, HJoyce, Ai, Y, King, S, Lipkin, SM, Shen, X
JournalCell Stem Cell
Volume18
Issue2
Pagination189-202
Date Published2016 Feb 4
ISSN1875-9777
Abstract

<p>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.</p>

DOI10.1016/j.stem.2016.01.006
Alternate JournalCell Stem Cell
PubMed ID26849305
PubMed Central IDPMC4751059
Grant ListR01 GM095990 / GM / NIGMS NIH HHS / United States
R01 GM114254 / GM / NIGMS NIH HHS / United States