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PMID: 23642368 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Research Support, U.S. Gov't, Non-P.H.S.

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

Cell stem cell ·Vol. 12 ·No. 5 ·2013-05-02 ·Pages 602-15

Bu P, Chen KY, Chen JH, Wang L, Walters J, Shin YJ, Goerger JP, Sun J, Witherspoon M, Rakhilin N, Li J, Yang H, Milsom J, Lee S, Zipfel W, Jin MM, Gümüş ZH, Lipkin SM, Shen X

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.

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,pathology Female Gene Expression Regulation, Neoplastic Humans Male Membrane Proteins/metabolism MicroRNAs/genetics,metabolism Middle Aged Neoplasm Staging Neoplastic Stem Cells/metabolism,pathology Nerve Tissue Proteins/metabolism Protein Transport Receptors, Notch/metabolism Signal Transduction/genetics Xenograft Model Antitumor Assays
Chemicals
MIRN34 microRNA, human Membrane Proteins MicroRNAs Nerve Tissue Proteins Numb protein, human Receptors, Notch
Authors & Affiliations
19 authors, click to expand affiliations / ORCID
Bu Pengcheng
School of Electrical and Computer Engineering, Cornell University, Ithaca, NY 14853, USA.
Chen Kai-Yuan
Chen Joyce Huan
Wang Lihua
Walters Jewell
Shin Yong Jun
Goerger Julian P
Sun Jian
Witherspoon Mavee
Rakhilin Nikolai
Li Jiahe
Yang Herman
Milsom Jeff
Lee Sang
Zipfel Warren
Jin Moonsoo M
Gümüş Zeynep H
Lipkin Steven M
Shen Xiling
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Article Info
Journal
Cell stem cell
Abbr.
Cell Stem Cell
ISSN
1875-9777
DOI
10.1016/j.stem.2013.03.002
Published
2013-05-02
Pages
602-15
Language
English
Region
United States
NLM ID
101311472
PMCID
PMC3646336
Subset
IM
Grants
NCI NIH HHS · R21CA162483 · United States
NIGMS NIH HHS · R01GM95990 · United States
NCI NIH HHS · R21 CA162483 · United States
NIGMS NIH HHS · R01 GM095990 · United States
NCI NIH HHS · R21CA153049 · United States
NCI NIH HHS · R21 CA153049 · United States
Corrections
CommentIn
PMID: 23642356
External Links
PubMed source DOI: 10.1016/j.stem.2013.03.002 PMC Full Text View journal details
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