A microRNA miR-34a-regulated bimodal switch targets Notch in colon cancer stem cells

Cell Stem Cell. 2013 May 2;12(5):602-15. doi: 10.1016/j.stem.2013.03.002.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

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

Substances

  • MIRN34 microRNA, human
  • Membrane Proteins
  • MicroRNAs
  • Nerve Tissue Proteins
  • Numb protein, human
  • Receptors, Notch