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

Abstract

The Wnt signalling pathway is essential for development and organogenesis1,2,3. 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 genes4,5,6. Mutations in CTNNB1 (encoding β-catenin) or APC (adenomatous polyposis coli) have been reported in human neoplasms including colon cancers and hepatocellular carcinomas7,8,9,10,11,12,13 (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.

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Figure 1: β-catenin distribution in hepatoma and primary HCC.
Figure 2: Homozygous deletions of AXIN1 and alterations in AXIN1 and CTNNB1.
Figure 3: TCF-4 specific transriptional activation by AXIN1 mutuation.
Figure 4: Growth inhibition of human hepatoma and colon cancer cells by Ad-APC or Ad-Axin.
Figure 5: Effects of Ad-Axin on intracellular β-catenin behaviour.
Figure 6: Induction of apoptosis in HCC and colon cancer cell lines by Ad-Axin.

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Acknowledgements

This work was supported by a “Research for the Future” Program Grant of The Japan Society for the Promotion of Science (96L00102).

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Correspondence to Yusuke Nakamura.

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Satoh, S., Daigo, Y., Furukawa, Y. et al. AXIN1 mutations in hepatocellular carcinomas, and growth suppression in cancer cells by virus-mediated transfer of AXIN1. Nat Genet 24, 245–250 (2000). https://doi.org/10.1038/73448

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