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Cancer Stem Cells

Embryonic NANOG Activity Defines Colorectal Cancer Stem Cells and Modulates through AP1- and TCF-dependent Mechanisms†‡§

  1. Elsayed E. Ibrahim1,2,3,6,
  2. Roya Babaei-Jadidi1,2,6,
  3. Anas Saadeddin1,2,6,
  4. Bradley Spencer-Dene4,6,
  5. Sina Hossaini1,2,6,
  6. Mohammed Abuzinadah1,2,6,
  7. Ningning Li1,2,6,
  8. Wakkas Fadhil5,6,
  9. Mohammad Ilyas4,6,
  10. Dominique Bonnet5,6,
  11. Abdolrahman S. Nateri1,2,6,¶,*

Article first published online: 20 SEP 2012

DOI: 10.1002/stem.1182

Issue

STEM CELLS

STEM CELLS

Volume 30, Issue 10, pages 2076–2087, October 2012

Additional Information

How to Cite

Ibrahim, E. E., Babaei-Jadidi, R., Saadeddin, A., Spencer-Dene, B., Hossaini, S., Abuzinadah, M., Li, N., Fadhil, W., Ilyas, M., Bonnet, D. and Nateri, A. S. (2012), Embryonic NANOG Activity Defines Colorectal Cancer Stem Cells and Modulates through AP1- and TCF-dependent Mechanisms. STEM CELLS, 30: 2076–2087. doi: 10.1002/stem.1182

Author Information

  1. 1

    Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom

  2. 2

    Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom

  3. 3

    Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt

  4. 4

    Experimental Histopathology Lab,Cancer Research U.K. London Research Institute, London, United Kingdom

  5. 5

    Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, United Kingdom

  6. 6

    Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom

  1. Telephone: +44-115-8231306; Fax: +44-115-8231137

*Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, School of Clinical Sciences, University of Nottingham, Nottingham, U.K.

  1. †

    Author contributions: E.E.I. and R.B.-J.: conception and design, collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; A.S. and B.S.-D.: collection and/or assembly of data, data analysis and interpretation, and final approval of manuscript; S.H., M.A., N.L., and W.F.: collection and/or assembly of data and final approval of manuscript; M.I. and D.B.: provision of study material or patients and final approval of manuscript; A.S.N.: conception and design, financial support, provision of study material or patients, manuscript writing, and final approval of manuscript.

  2. ‡

    Disclosure of potential conflicts of interest is found at the end of this article.

  3. §

    First published online in STEM CELLSEXPRESS July 31, 2012

  4. Telephone: +44-115-8231306; Fax: +44-115-8231137

Publication History

  1. Issue published online: 20 SEP 2012
  2. Article first published online: 20 SEP 2012
  3. Accepted manuscript online: 31 JUL 2012 12:36PM EST
  4. Manuscript Accepted: 7 JUL 2012
  5. Manuscript Revised: 19 JUN 2012
  6. Manuscript Received: 17 FEB 2012

Funded by

  • Ph.D. studentship
  • Medical Research Council. Grant Number: G0700763

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Keywords:

  • NANOG1;
  • β-Catenin;
  • c-JUN;
  • Cancer stem cell

Abstract

Embryonic NANOG (NANOG1) is considered as an important regulator of pluripotency while NANOGP8 (NANOG-pseudogene) plays a role in tumorigenesis. Herein, we show NANOG is expressed from both NANOG1 and NANOGP8 in human colorectal cancers (CRC). Enforced NANOG1-expression increases clonogenic potential and tumor formation in xenograft models, although it is expressed only in a small subpopulation of tumor cells and is colocalized with endogenous nuclear β-cateninHigh. Moreover, single NANOG1-CRCs form spherical aggregates, similar to the embryoid body of embryonic stem cells (ESCs), and express higher levels of stem-like Wnt-associated target genes. Furthermore, we show that NANOG1-expression is positively regulated by c-JUN and β-catenin/TCF4. Ectopic expression of c-Jun in murine ApcMin/+-ESCs results in the development of larger xenograft tumors with higher cell density compared to controls. Chromatin immunoprecipitation assays demonstrate that c-JUN binds to the NANOG1-promoter via the octamer M1 DNA element. Collectively, our data suggest that β-Catenin/TCF4 and c-JUN together drive a subpopulation of CRC tumor cells that adopt a stem-like phenotype via the NANOG1-promoter. STEM Cells2012;30:2076–2087

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