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

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.

Wnt signaling in disease and in development

“…Mutations in β-catenin and APC have also been found in sporadic colon cancers and a large variety of other tumor types (reviewed in [20]). Loss-of-function mutations in Axin have been found in hepatocellular carcinomas [38]. These examples demonstrate that the uncoupling of normal β-catenin regulation from Wnt signaling control is an important event in the genesis of many cancers.…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…Perturbations in the levels of Axin, APC, β-catenin, LEF1 or TCF4, for example, contribute to the initiation and/or progression of several different types of cancer [7][8][9][10][11][12]. It is therefore not surprising that so much effort has gone into the development of new drugs based on our knowledge of Wnt signaling to treat disease.…”

Dysregulation of growth factor signaling in human hepatocellular carcinoma

“…Instead, nuclear accumulation is in part explained by stabilizing point mutations and deletions in the N-terminal phosphorylation domain of b-catenin, which is observed in 19-44% of all cases (de La Coste et al, 1998;Miyoshi et al, 1998;Cui et al, 2003;Prange et al, 2003;Fujito et al, 2004). In addition, mutational inactivation by deletions, missense and nonsense mutations has been described for axin-1 (5-14%), predominantly in the region responsible for b-catenin and GSK-3b interactions (Satoh et al, 2000;Ishizaki et al, 2004). Equally, axin-2 (Conductin), which also contains binding sites for b-catenin and GSK-3b, exhibits mutations in 3-10% of the HCCs (Taniguchi et al, 2002;Ishizaki et al, 2004).…”