A MicroRNA MiR-34a-regulated Bimodal Switch Targets Notch in Colon Cancer Stem Cells

Overview

Journal Cell Stem Cell

Publisher Cell Press

Specialty Cell Biology

Date 2013 May 7

PMID 23642368

Citations 186

Authors

Pengcheng Bu

Kai-Yuan Chen

Joyce Huan Chen

Lihua Wang

Jewell Walters

Yong Jun Shin

Julian P Goerger

Jian Sun

Mavee Witherspoon

Nikolai Rakhilin

Jiahe Li

Herman Yang

Jeff Milsom

Sang Lee

Warren Zipfel

Moonsoo M Jin

Zeynep H Gumus

Steven M Lipkin

Xiling Shen

Affiliations

Soon will be listed here.

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.

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