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J R Soc Interface. 2014 Dec 6;11(101):20140962. doi: 10.1098/rsif.2014.0962.

Towards elucidating the connection between epithelial-mesenchymal transitions and stemness.

Author information

1
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA.
2
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Department of Chemistry, Rice University, Houston, TX 77005-1827, USA.
3
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA.
4
Department of Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA Metastasis Research Center, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
5
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Department of Bioengineering, Rice University, Houston, TX 77005-1827, USA Department of Physics and Astronomy, Rice University, Houston, TX 77005-1827, USA herbert.levine@rice.edu.
6
Center for Theoretical Biological Physics, Rice University, Houston, TX 77005-1827, USA Department of Biosciences, Rice University, Houston, TX 77005-1827, USA School of Physics and Astronomy and The Sagol School of Neuroscience, Tel-Aviv University, Tel-Aviv 69978, Israel eshel@rice.edu.

Abstract

Epithelial cells undergoing epithelial-to-mesenchymal transitions have often been shown to behave as cancer stem cells, but the precise molecular connection remains elusive. At the genetic level, stemness is governed by LIN28/let-7 double inhibition switch, whereas EMT/MET is controlled by miR-200/ZEB double inhibition circuit and LIN28 is inhibited by miR-200, coupling the two modules. Here, using a specially devised theoretical framework to investigate the dynamics of the LIN28/let-7 system, we show that it can operate as a three-way switch (between low, high and intermediate LIN28 levels termed the D, U and hybrid D/U states) similar to the three-way operation of the miR-200/ZEB circuit that allows for the existence of a hybrid epithelial/mesenchymal (E/M) phenotype. We find significant correspondence between the existence of the three states of the two circuits: E-D, M-U and E/M-D/U. Incorporating the activation of OCT4 by LIN28, we find that the hybrid E/M phenotype has high likelihood (when compared with either the E or M states) to gain stemness. Combining the LIN28/let-7 regulation by NF-κB and c-MYC, we find that NF-κB, but not c-MYC, elevates the likelihood of E/M phenotype to gain stemness. Our results are consistent with emerging concept that partial EMT can lead to stemness.

KEYWORDS:

LIN28/let-7; cancer stem cells; epithelial–mesenchymal transition; hybrid epithelial/mesenchymal phenotype; stemness

PMID:
25339690
PMCID:
PMC4223923
DOI:
10.1098/rsif.2014.0962
[Indexed for MEDLINE]
Free PMC Article

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