A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells. Academic Article uri icon

Overview

MeSH

  • Aged
  • Aged, 80 and over
  • Asymmetric Cell Division
  • Carcinogenesis
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Proliferation
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Membrane Proteins
  • Middle Aged
  • Neoplasm Staging
  • Nerve Tissue Proteins
  • Protein Transport
  • Signal Transduction
  • Xenograft Model Antitumor Assays

MeSH Major

  • Colonic Neoplasms
  • MicroRNAs
  • Neoplastic Stem Cells
  • Receptors, Notch

abstract

  • microRNAs regulate developmental cell-fate decisions, tissue homeostasis, and oncogenesis in distinct ways relative to proteins. Here, we show that the tumor suppressor microRNA miR-34a is a cell-fate determinant in early-stage dividing colon cancer stem cells (CCSCs). In pair-cell assays, miR-34a distributes at high levels in differentiating progeny, whereas low levels of miR-34a demarcate self-renewing CCSCs. Moreover, miR-34a loss of function and gain of function alter the balance between self-renewal versus differentiation both in vitro and in vivo. Mechanistically, miR-34a sequesters Notch1 mRNA to generate a sharp threshold response where a bimodal Notch signal specifies the choice between self-renewal and differentiation. In contrast, the canonical cell-fate determinant Numb regulates Notch levels in a continuously graded manner. Altogether, our findings highlight a unique microRNA-regulated mechanism that converts noisy input into a toggle switch for robust cell-fate decisions in CCSCs. Copyright © 2013 Elsevier Inc. All rights reserved.

publication date

  • May 2, 2013

has subject area

  • Aged
  • Aged, 80 and over
  • Asymmetric Cell Division
  • Carcinogenesis
  • Cell Differentiation
  • Cell Line, Tumor
  • Cell Lineage
  • Cell Proliferation
  • Colonic Neoplasms
  • Female
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Male
  • Membrane Proteins
  • MicroRNAs
  • Middle Aged
  • Neoplasm Staging
  • Neoplastic Stem Cells
  • Nerve Tissue Proteins
  • Protein Transport
  • Receptors, Notch
  • Signal Transduction
  • Xenograft Model Antitumor Assays

Research

keywords

  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3646336

Digital Object Identifier (DOI)

  • 10.1016/j.stem.2013.03.002

PubMed ID

  • 23642368

Additional Document Info

start page

  • 602

end page

  • 615

volume

  • 12

number

  • 5