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, Pengcheng; Wang, Lihua; Chen, Kai-Yuan; Srinivasan, Tara; Murthy, Preetish Kadur Lakshminarasimha; Tung, Kuei-Ling; ... Shen, Xiling (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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Hawkins Family Associate Professor
Dr. Shen’s research interests lie at precision medicine and systems biology. His lab integrates engineering, computational and biological techniques to study cancer, stem cells, microbiota and the nervous system in the gut. This multidisciplinary work has been instrumental in initiating several translational clinical trials in precision therapy. He is the director of the Woo Center for Big Data and Precision Health (DAP) and a core member of the Center for Genomics and Computational Biolog