AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1.
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.
Satoh
S
S
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Daigo
Y
Y
Furukawa
Y
Y
Kato
T
T
Miwa
N
N
Nishiwaki
T
T
Kawasoe
T
T
Ishiguro
H
H
Fujita
M
M
Tokino
T
T
Sasaki
Y
Y
Imaoka
S
S
Murata
M
M
Shimano
T
T
Yamaoka
Y
Y
Nakamura
Y
Y
D025601:Adenomatous Polyposis Coli Protein; D000256:Adenoviridae / Q000235:genetics; D017209:Apoptosis / Q000235:genetics; D060466:Axin Protein; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000502:physiology; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism*; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism / Q000502:physiology; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D020022:Genetic Predisposition to Disease; D005822:Genetic Vectors / Q000235:genetics; D038362:Glycogen Synthase Kinase 3; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D046911:Macromolecular Substances; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D018807:Polymorphism, Single-Stranded Conformational; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012097:Repressor Proteins; D015398:Signal Transduction / Q000502:physiology*; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection; D014407:Tumor Cells, Cultured; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C555451:AXIN1 protein, human; D025601:Adenomatous Polyposis Coli Protein; D060466:Axin Protein; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004273:DNA, Neoplasm; D046911:Macromolecular Substances; D009363:Neoplasm Proteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D011993:Recombinant Fusion Proteins; D012097:Repressor Proteins; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3