title: A miR-34a-Numb Feedforward Loop Triggered by Inflammation Regulates Asymmetric Stem Cell Division in Intestine and Colon Cancer.
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.
authors: 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.
authors: Pengcheng
authors: P
authors: Bu
authors: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Lihua
authors: L
authors: Wang
authors: School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Kai-Yuan
authors: KY
authors: Chen
authors: Department of Biomedical Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Tara
authors: T
authors: Srinivasan
authors: School of Mechanical Aerospace Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Preetish Kadur Lakshminarasimha
authors: PK
authors: Murthy
authors: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Kuei-Ling
authors: KL
authors: Tung
authors: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Anastasia Kristine
authors: AK
authors: Varanko
authors: Meyer Cancer Center, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Huanhuan Joyce
authors: HJ
authors: Chen
authors: School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Yiwei
authors: Y
authors: Ai
authors: Department of Biological and Environmental Engineering, Cornell University, Ithaca, NY 14853, USA.
authors: Sarah
authors: S
authors: King
authors: Departments of Medicine, Genetic Medicine, and Surgery, Weill Cornell Medical College, New York, NY 10021, USA.
authors: Steven M
authors: SM
authors: Lipkin
authors: 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.
authors: Xiling
authors: X
authors: Shen
mesh_terms: D000818:Animals; D060049:Asymmetric Cell Division / Q000187:drug effects; D001483:Base Sequence; D002454:Cell Differentiation / Q000187:drug effects; D019070:Cell Lineage / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D055785:Gene Knockdown Techniques; D007249:Inflammation / Q000473:pathology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008969:Molecular Sequence Data; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D051880:Receptors, Notch / Q000378:metabolism; D013312:Stress, Physiological / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: C551848:MIRN34a microRNA, mouse; D008565:Membrane Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; C106293:Numb protein, mouse; D051880:Receptors, Notch; D014409:Tumor Necrosis Factor-alpha