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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Tsuda, M. et al. The cell-surface proteoglycan Dally regulates Wingless signalling in Drosophila. Nature 400, 276– 280 (1999).
Itoh, K., Krupnik, V.E. & Sokol, S.Y. Axis determination in Xenopus involves biochemical interactions of axin, glycogen synthase kinase 3 and β-catenin. Curr. Biol. 8, 591–594 ( 1998).
Lee, Y.J., Swencki, B., Shoichet, S. & Shivdasani, R.A. A possible role for the high mobility group box transcription factor TCF4 in vertebrate gut epithelial cell differentiation. J. Biol. Chem. 274, 1566–1572 ( 1999).
Morin, P.J. et al. Activation of β-catenin-Tcf signaling in colon cancer by mutations in β-catenin or APC. Science 275, 1787–1790 (1997).
He, T.C. et al. Identification of c-MYC as a target of the APC pathway. Science. 281, 1509–1512 (1998).
Tetsu, O. & McCormick, F. β-catenin regulates expression of cyclin D1 in colon carcinoma cells. Nature 398, 422–426 (1999).
Fukuchi, T. et al. β-catenin mutation in carcinoma of the uterine endometrium . Cancer Res. 58, 3526– 3528 (1998).
Chan, E.F., Gat, U., McNiff, J.M. & Fuchs, E. A common human skin tumour is caused by activating mutations in β-catenin. Nature Genet. 21, 410–413 ( 1999).
Miyoshi, Y. et al. Activation of the β-catenin gene in primary hepatocellular carcinomas by somatic alterations involving exon 3. Cancer Res. 58, 2524–2527 ( 1998).
Voeller, H.J., Truica, C.I. & Gelmann, E.P. β-catenin mutations in human prostate cancer . Cancer Res. 58, 2520– 2523 (1998).
Zurawel, R.H., Chiappa, S.A., Allen, C. & Raffel, C. Sporadic medulloblastomas contain oncogenic β-catenin mutations. Cancer Res. 58, 896–899 (1998).
Iwao, K. et al. Activation of the β-catenin gene by interstitial deletions involving exon 3 in primary colorectal carcinomas without adenomatous polyposis coli mutations. Cancer Res. 58, 1021– 1026 (1998).
de La Coste, A. et al. Somatic mutations of the β-catenin gene are frequent in mouse and human hepatocellular carcinomas. Proc. Natl Acad. Sci. USA 95, 8847–8851 ( 1998).
Ihara, A., Koizumi, H., Hashizume, R. & Uchikoshi, T. Expression of epithelial cadherin and α- and β-catenins in nontumoral livers and hepatocellular carcinomas. Hepatology 23 , 1441–1447 (1996).
Ding, S.F. et al. The putative tumor suppressor gene on chromosome 5q for hepatocellular carcinoma is distinct from the MCC and APC genes. Cancer Detect. Prev. 17, 405–409 ( 1993).
Smalley, M.J. et al. Interaction of axin and Dvl-2 proteins regulates Dvl-2-stimulated TCF-dependent transcription. EMBO J. 18, 2823–2835 (1999).
Hart, M.J., de los Santos, R., Albert, I.N., Rubinfeld, B. & Polakis, P. Downregulation of β-catenin by human Axin and its association with the APC tumor suppressor, β-catenin and GSK3β. Curr. Biol. 8, 573– 581 (1998).
Nakamura, T. et al. Axin, an inhibitor of the Wnt signalling pathway, interacts with β-catenin, GSK-3β and APC and reduces the β-catenin level . Genes Cells 3, 395–403 (1998).
Korinek, V. et al. Constitutive transcriptional activation by a β-catenin-Tcf complex in APC−/− colon carcinoma. Science 275, 1784–1787 (1997).
Nakamura, Y. Cleaning up on β-catenin. Nature Med. 3, 499–500 (1997).
Orford, K., Orford, C.C. & Byers, S.W. Exogenous expression of β-catenin regulates contact inhibition, anchorage-independent growth, anoikis, and radiation-induced cell cycle arrest. J. Cell Biol. 146, 855– 868 (1999).
Zhang, Z. et al. Destabilization of β-catenin by mutations in presenilin-1 potentiates neuronal apoptosis. Nature 395, 698–702 (1998).
Morin, P.J., Vogelstein, B. & Kinzler, K.W. Apoptosis and APC in colorectal tumorigenesis. Proc. Natl Acad. Sci. USA 93, 7950– 7954 (1996).
Nagai, H. et al. Comprehensive allelotyping of human hepatocellular carcinoma . Oncogene 14, 2927–2933 (1997)
Polakis, P. The adenomatous polyposis coli (APC) tumor suppressor. Biochim. Biophys. Acta 1332, F127–F147 (1997).
Takahashi, M. et al. Long term correction of bilirubin-UDP-glucuronosyltransferase deficiency in Gunn rats by administration of a recombinant adenovirus during the neonatal period. J. Biol. Chem. 271, 26536–26542 (1996).
McGrory, W.J., Bautista, D.S. & Graham, F.L. A simple technique for the rescue of early region I mutations into infectious human adenovirus type 5. Virology 163, 614–617 (1988).
Van de Wetering, M., Castrop, J., Korinek, V. & Clevers, H. Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties. Mol. Cell. Biol. 16, 745–752 (1996).
Acknowledgements
This work was supported by a “Research for the Future” Program Grant of The Japan Society for the Promotion of Science (96L00102).
Author information
Authors and Affiliations
Corresponding author
Supplementary information
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/73448
This article is cited by
-
The scaffold protein AXIN1: gene ontology, signal network, and physiological function
Cell Communication and Signaling (2024)
-
A combined bioinformatics and experimental approach identifies RMI2 as a Wnt/β-catenin signaling target gene related to hepatocellular carcinoma
BMC Cancer (2023)
-
β-catenin-IRP2-primed iron availability to mitochondrial metabolism is druggable for active β-catenin-mediated cancer
Journal of Translational Medicine (2023)
-
Hepatocellular carcinoma: molecular mechanism, targeted therapy, and biomarkers
Cancer and Metastasis Reviews (2023)
-
Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities
Signal Transduction and Targeted Therapy (2022)