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

Authors

  • Elsayed E. Ibrahim,

    1. Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom
    2. Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom
    3. Department of Zoology, Faculty of Science, Mansoura University, Mansoura, Egypt
    4. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Roya Babaei-Jadidi,

    1. Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom
    2. Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom
    3. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Anas Saadeddin,

    1. Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom
    2. Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom
    3. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Bradley Spencer-Dene,

    1. Experimental Histopathology Lab,Cancer Research U.K. London Research Institute, London, United Kingdom
    2. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Sina Hossaini,

    1. Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom
    2. Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom
    3. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Mohammed Abuzinadah,

    1. Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom
    2. Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom
    3. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Ningning Li,

    1. Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom
    2. Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom
    3. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Wakkas Fadhil,

    1. Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, United Kingdom
    2. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Mohammad Ilyas,

    1. Experimental Histopathology Lab,Cancer Research U.K. London Research Institute, London, United Kingdom
    2. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Dominique Bonnet,

    1. Division of Pathology, School of Molecular Medical Sciences, University of Nottingham, Nottingham, United Kingdom
    2. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
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  • Abdolrahman S. Nateri

    Corresponding author
    1. Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, University of Nottingham, Nottingham, United Kingdom
    2. Nottingham Digestive Diseases Centre, School of Clinical Sciences, University of Nottingham, Nottingham, United Kingdom
    3. Haematopoietic Stem Cell Lab, Cancer Research U.K. London Research Institute, London, United Kingdom
    • Cancer Genetics and Stem Cell Group, Division of Pre-Clinical Oncology, School of Clinical Sciences, University of Nottingham, Nottingham, U.K.

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    • Telephone: +44-115-8231306; Fax: +44-115-8231137


  • 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.

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

  • §

    First published online in STEM CELLSEXPRESS July 31, 2012

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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