A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.
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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.
Asymmetric Cell Division
Gene Knockdown Techniques
Molecular Sequence Data
Neoplastic Stem Cells
Nerve Tissue Proteins
Tumor Necrosis Factor-alpha
Published Version (Please cite this version)10.1016/j.stem.2016.01.006
Publication InfoBu, P; Wang, L; Chen, KY; Srinivasan, T; Murthy, PK; Tung, KL; ... Shen, X (2016). A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer. Cell Stem Cell, 18(2). pp. 189-202. 10.1016/j.stem.2016.01.006. Retrieved from https://hdl.handle.net/10161/11645.
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