Functional Evidence that the Self-Renewal Gene NANOG Regulates Human Tumor Development

Authors

  • Collene R. Jeter,

    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
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  • Mark Badeaux,

    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
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  • Grace Choy,

    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
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  • Dhyan Chandra,

    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
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  • Lubna Patrawala,

    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
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  • Can Liu,

    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
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  • Tammy Calhoun-Davis,

    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
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  • Holm Zaehres,

    1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute and Harvard Medical School, Division of Hematology/Oncology Children's Hospital, Boston, Massachusetts, USA
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  • George Q. Daley,

    1. Department of Biological Chemistry and Molecular Pharmacology, Harvard Stem Cell Institute and Harvard Medical School, Division of Hematology/Oncology Children's Hospital, Boston, Massachusetts, USA
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  • Dean G. Tang

    Corresponding author
    1. Department of Carcinogenesis, University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas, USA
    • Department of Carcinogenesis, University of Texas, M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, TX 78957, USA
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    • Telephone: +512-237-9575; Fax: 512-237-2475


  • Author contributions: C.J.: conception and design, collection and assembly of data, data analysis and interpretation, manuscript writing; M.B., G.C., D.C., L.P., C.L., T.C.: collection and assembly of data; H.Z., G.D.: provision of study material; D.T.: conception and design, data analysis and interpretation, manuscript writing, final approval of manuscript.

  • First published online in Stem CellsExpress February 5, 2009

Abstract

Tumor development has long been known to resemble abnormal embryogenesis. The embryonic stem cell (ESC) self-renewal gene NANOG is purportedly expressed by some epithelial cancer cells but a causal role in tumor development has remained unclear. Here, we provide compelling evidence that cultured cancer cells, as well as xenograft- and human primary prostate cancer cells express a functional variant of NANOG. NANOG mRNA in cancer cells is derived predominantly from a retrogene locus termed NANOGP8. NANOG protein is detectable in the nucleus of cancer cells and is expressed higher in patient prostate tumors than matched benign tissues. NANOGP8 mRNA and/or NANOG protein levels are enriched in putative cancer stem/progenitor cell populations. Importantly, extensive loss-of-function analysis reveals that RNA interference-mediated NANOG knockdown inhibits tumor development, establishing a functional significance for NANOG expression in cancer cells. Nanog short hairpin RNA transduced cancer cells exhibit decreased long-term clonal and clonogenic growth, reduced proliferation and, in some cases, altered differentiation. Thus, our results demonstrate that NANOG, a cell-fate regulatory molecule known to be important for ESC self-renewal, also plays a novel role in tumor development. Stem Cells 2009;27:993–1005

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