AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1

• Published in: Nature genetics Vol. 24; no. 3; pp. 245 - 250
• Main Authors: Nakamura, Yusuke, Satoh, Seiji, Daigo, Yataro, Furukawa, Yoichi, Kato, Tatsushi, Miwa, Nobutomo, Nishiwaki, Tadashi, Kawasoe, Teru, Ishiguro, Hideyuki, Fujita, Manabu, Tokino, Takashi, Sasaki, Yo, Imaoka, Shingi, Murata, Masaru, Shimano, Takashi, Yamaoka, Yoshio
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group 01-03-2000
• Subjects: adenomatous polyposis coli; Adenomatous Polyposis Coli Protein; Adenoviridae - genetics; APC gene; Apoptosis - genetics; Axin Protein; AXIN1 gene; b-catenin; beta Catenin; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - physiology; Cancer cells; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - metabolism; Cell physiology; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Cells; Colorectal carcinoma; Colorectal Neoplasms - genetics; Colorectal Neoplasms - metabolism; Colorectal Neoplasms - pathology; CTNNB1 gene; Cytoskeletal Proteins - metabolism; Cytoskeletal Proteins - physiology; Deoxyribonucleic acid; Diagnosis; DNA; DNA Mutational Analysis; DNA, Neoplasm - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic; Gene mutations; Genes, APC; Genetic aspects; Genetic Predisposition to Disease; Genetic Vectors - genetics; Genetics; Glycogen Synthase Kinase 3; Hepatoma; Humans; Identification and classification; Kinases; Liver cancer; Liver Neoplasms - genetics; Liver Neoplasms - metabolism; lymphocyte enhancer-binding factor; Lymphocytes; Macromolecular Substances; Molecular and cellular biology; Mutation; Neoplasm Proteins - genetics; Neoplasm Proteins - physiology; Phosphorylation; Physiological aspects; Polymorphism, Single-Stranded Conformational; Protein Structure, Tertiary; Proteins - genetics; Proteins - physiology; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - physiology; Recombinant Fusion Proteins - physiology; Repressor Proteins; Signal Transduction - physiology; TCF Transcription Factors; Trans-Activators; Transcription Factor 7-Like 2 Protein; Transcription Factors - metabolism; Transfection; Tumor Cells, Cultured; Tumors; Wnt protein; Wnt Proteins; Zebrafish Proteins; Japan; Human; Adenoviridae; Hepatic disease; Hepatocellular carcinoma; Malignant tumor; Gene expression; Carcinogenesis; Genetic transfer; Virus; Case study; Signal transduction; Cell line; Mutation; Catenin; Vector; Apoptosis
• ISSN: 1061-4036; 1546-1718
• DOI: 10.1038/73448

The Wnt signalling pathway is essential for development and organogenesis. Wnt signalling stabilizes β-catenin, which accumulates in the cytoplasm, binds to T-cell factor (TCF; also known as lymphocyte enhancer-binding factor, LEF) and then upregulates downstream genes. Mutations in CTNNB1 (encoding β-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas (HCCs). Because HCCs tend to show accumulation of β-catenin more often than mutations in CTNNB1 , we looked for mutations in AXIN1, encoding a key factor for Wnt signalling, in 6 HCC cell lines and 100 primary HCCs. Among the 4 cell lines and 87 HCCs 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 β-catenin in nuclei. Adenovirus mediated gene transfer of wild-type AXIN1 induced apoptosis in hepatocellular and colorectal cancer cells that had accumulated β-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.