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Cell Stem Cell. 2016 Feb 4;18(2):189-202. doi: 10.1016/j.stem.2016.01.006.

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

Author information

1
School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA. Electronic address: pb345@cornell.edu.
2
Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
3
School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.
4
Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
5
School of Mechanical Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA.
6
Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
7
Departments of Medicine, Genetic Medicine, and Surgery, Weill Cornell Medical College, New York, NY 10021, USA.
8
School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA; Department of Biomedical Engineering, Duke University, Durham, NC 27708, USA. Electronic address: xs37@duke.edu.

Abstract

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.

PMID:
26849305
PMCID:
PMC4751059
DOI:
10.1016/j.stem.2016.01.006
[Indexed for MEDLINE]
Free PMC Article
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