Abstract
The Wnt signaling pathway is essential for development and organogenesis. Wnt signaling stabilizes beta-catenin, which accumulates in the cytoplasm, binds to 1-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes. Mutations in CTNNB1 (encoding beta-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas (HCCs). Because HCC5 tend to show accumulation of beta-catenin more often than mutations in CTNNB1, we looked for mutations in AXIN1, encoding a key factor for Wnt signaling, in 6 HCC cell lines and 100 primary HCC5. Among the 4 cell lines and 87 HCC5 in which we did not detect CTNNB1 mutations, we identified AXIN1 mutations in 3 cell lines and 6 mutations in 5 of the primary HCCs. In cell lines containing mutations in either gene, we observed increased DNA binding of TCF associated with beta-catenin in nuclei. Adenovirus mediated gene transfer of wild-type AXINI induced apoptosis in hepatocellular and colorectal cancer cells that had accumulated beta-catenin as a consequence of either APC, CTNNB1 or AXIN1 mutation, suggesting that axin may be an effective therapeutic molecule for suppressing growth of hepatocellular and colorectal cancers.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenomatous Polyposis Coli Protein
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Adenoviridae / genetics
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Apoptosis / genetics
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Axin Protein
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Calcium-Calmodulin-Dependent Protein Kinases / physiology
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / metabolism*
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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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Cytoskeletal Proteins / metabolism
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Cytoskeletal Proteins / physiology
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DNA Mutational Analysis
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DNA, Neoplasm / genetics*
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Gene Expression Regulation, Neoplastic*
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Genes, APC
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Genetic Predisposition to Disease
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Genetic Vectors / genetics
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Glycogen Synthase Kinase 3
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Humans
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Liver Neoplasms / genetics
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Liver Neoplasms / metabolism*
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Macromolecular Substances
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Neoplasm Proteins / genetics
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Neoplasm Proteins / physiology*
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Polymorphism, Single-Stranded Conformational
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Protein Structure, Tertiary
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Proteins / genetics
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Proteins / physiology*
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Proto-Oncogene Proteins / genetics
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Proto-Oncogene Proteins / physiology
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Recombinant Fusion Proteins / physiology
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Repressor Proteins*
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Signal Transduction / physiology*
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TCF Transcription Factors
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Trans-Activators*
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Transcription Factor 7-Like 2 Protein
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Transcription Factors / metabolism
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Transfection
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Tumor Cells, Cultured
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Wnt Proteins
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Zebrafish Proteins*
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beta Catenin
Substances
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AXIN1 protein, human
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Adenomatous Polyposis Coli Protein
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Axin Protein
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CTNNB1 protein, human
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Cytoskeletal Proteins
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DNA, Neoplasm
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Macromolecular Substances
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Neoplasm Proteins
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Proteins
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Proto-Oncogene Proteins
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Recombinant Fusion Proteins
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Repressor Proteins
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TCF Transcription Factors
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TCF7L2 protein, human
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Trans-Activators
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Transcription Factor 7-Like 2 Protein
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Transcription Factors
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Wnt Proteins
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Zebrafish Proteins
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beta Catenin
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Calcium-Calmodulin-Dependent Protein Kinases
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Glycogen Synthase Kinase 3