Satoh S, Daigo Y, Furukawa Y, Kato T, Miwa N, Nishiwaki T, Kawasoe T, Ishiguro H, Fujita M, Tokino T, Sasaki Y, Imaoka S, Murata M, Shimano T, Yamaoka Y, Nakamura Y
Laboratory of Molecular Medicine, Human Genome Center, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Nat Genet. 2000 Mar;24(3):245-50. doi: 10.1038/73448.
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信号通路对于发育和器官形成至关重要。Wnt信号使β-连环蛋白稳定，β-连环蛋白在细胞质中积累，与1-细胞因子（TCF；也称为淋巴细胞增强子结合因子，LEF）结合，然后上调下游基因。在包括结肠癌和肝细胞癌（HCC）在内的人类肿瘤中，已报道CTNNB1（编码β-连环蛋白）或APC（腺瘤性息肉病 coli）发生突变。由于HCC5往往比CTNNB1突变更常表现出β-连环蛋白的积累，我们在6种HCC细胞系和100例原发性HCC5中寻找AXIN1（编码Wnt信号的关键因子）的突变。在我们未检测到CTNNB1突变的4种细胞系和87例HCC5中，我们在3种细胞系中鉴定出AXIN1突变，在5例原发性HCC中有6个突变。在任一基因含有突变的细胞系中，我们观察到细胞核中与β-连环蛋白相关的TCF的DNA结合增加。野生型AXINI的腺病毒介导的基因转移在因APC、CTNNB1或AXIN1突变而积累了β-连环蛋白的肝细胞癌和结肠癌细胞中诱导凋亡，这表明axin可能是抑制肝细胞癌和结肠直肠癌生长的有效治疗分子。
