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-catenin(High) . 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 Apc(Min/+) -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.
Copyright © 2012 AlphaMed Press.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Protein Complex 1 / genetics
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Adaptor Protein Complex 1 / metabolism*
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Animals
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / metabolism*
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Binding Sites
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Cell Transformation, Neoplastic
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Colorectal Neoplasms / genetics
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Colorectal Neoplasms / metabolism*
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Colorectal Neoplasms / pathology
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Female
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Gene Expression Regulation, Neoplastic
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Homeodomain Proteins / genetics
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Homeodomain Proteins / metabolism*
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Humans
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JNK Mitogen-Activated Protein Kinases / genetics
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JNK Mitogen-Activated Protein Kinases / metabolism
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Male
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Mice
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Nanog Homeobox Protein
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Neoplasm Transplantation
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Neoplastic Stem Cells / metabolism*
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Neoplastic Stem Cells / pathology
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Promoter Regions, Genetic
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Protein Binding
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Pseudogenes
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Signal Transduction / genetics
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Transcription Factor 4
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Transcription Factors / genetics
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Transcription Factors / metabolism*
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Wnt Proteins / genetics
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Wnt Proteins / metabolism
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beta Catenin / genetics
Substances
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Adaptor Protein Complex 1
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Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
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CTNNB1 protein, human
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Homeodomain Proteins
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NANOG protein, human
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Nanog Homeobox Protein
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TCF4 protein, human
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Transcription Factor 4
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Transcription Factors
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Wnt Proteins
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beta Catenin
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JNK Mitogen-Activated Protein Kinases