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


Autoria(s): Bu, P; Wang, L; Chen, KY; Srinivasan, T; Murthy, PK; Tung, KL; Varanko, AK; Chen, HJ; Ai, Y; King, S; Lipkin, SM; Shen, X
Cobertura

United States

Data(s)

04/02/2016

Resumo

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.

Formato

189 - 202

Identificador

http://www.ncbi.nlm.nih.gov/pubmed/26849305

S1934-5909(16)00007-2

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

http://hdl.handle.net/10161/11645

1875-9777

Idioma(s)

ENG

Relação

Cell Stem Cell

10.1016/j.stem.2016.01.006

Tipo

Journal Article