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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Bu, P; Wang, L; Chen, K-Y; Srinivasan, T; Murthy, PKL; Tung, K-L; Varanko, AK; Chen, HJ; Ai, Y; King, S; Lipkin, SM; Shen, X

Published Date

  • February 2016

Published In

Volume / Issue

  • 18 / 2

Start / End Page

  • 189 - 202

PubMed ID

  • 26849305

Pubmed Central ID

  • 26849305

Electronic International Standard Serial Number (EISSN)

  • 1875-9777

International Standard Serial Number (ISSN)

  • 1934-5909

Digital Object Identifier (DOI)

  • 10.1016/j.stem.2016.01.006

Language

  • eng