Role of b-Catenin Wingless/Wnt Pathway in Liver Carcinog

对于人肝细胞癌（HCC），已经提出了两种肝癌发展机制。一个涉及通过激活b-连环蛋白来破坏Wingless/Wnt信号通路，而另一个的特征在于基因组不稳定性。我们以前已经产生了一些肝癌的转基因小鼠模型。在这里，我们调查的相关性，这两个分子途径，小鼠肝癌。通过PCR和测序筛选分析来自c-myc、TGF-α、E2 F-1、c-myc/TGF-α和c-myc/E2 F-1转基因小鼠的大量肿瘤性肝病变的β-连环蛋白突变和缺失。此外，作为衡量的b-连环蛋白激活，亚细胞定位的蛋白质进行了评估，免疫组织化学。RAPD方法被用来评估整体基因组的不稳定性，在癌前病变和肿瘤病变和染色体位点的基因组改变的影响，通过微卫星分析确定。来自转基因小鼠系的肝肿瘤可以分为两类。第一类，最好的例子是c-myc/E2 F-1转基因系，其特征在于在相对稳定的基因组存在下高频率的β-连环蛋白激活。连环蛋白的核积聚仅限于具有分化良好的嗜酸性表型的癌前病变和肿瘤病变。第二类，以c-myc/TGF-α转基因系为代表，从早期发育异常阶段开始显示广泛的基因组不稳定性和低速率的β-连环蛋白激活。在该肝癌模型中检测到在染色体1、2、4、5、6、7、8、9、12、14、15和X处的复发性杂合性丢失。这些数据表明，在人HCC中重现了针对人HCC描述的类似分子途径。

Two mechanisms of liver cancer development have been proposed for human hepatocellular carcinoma (HCC). One involves the disruption of the Wingless/Wnt signaling pathway by activation of b-catenin, while the other is characterized by genomic instability. We have previously generated a number of transgenic mouse models of liver cancer. Here we investigate the relevance of these two molecular pathways to murine hepatocarcinogenesis. A large number of neoplastic liver lesions from c-myc, TGF-a, E2F-1, c-myc/TGF-a and c-myc/E2F-1 transgenic mice were analyzed for b-catenin mutations and deletions by PCR and sequencing screening. Also, as a measure of b-catenin activation, the subcellular localization of the protein was evaluated by immunohistochemistry. The RAPD method was used to assess the overall genomic instability in preneoplastic and neoplastic lesions and chromosomal loci affected by genomic alterations were determined by microsatellite analysis. Liver tumors from the transgenic mouse lines could be divided in two categories. The first category, best exemplified by the c-myc/E2F-1 transgenic line, was characterized by high frequency of b-catenin activation in the presence of a relatively stable genome. The nuclear accumulation of b-catenin was limited to preneoplastic and neoplastic lesions with a well-differentiated eosinophilic phenotype. The second category, represented by c-myc/TGF-a transgenic line, displayed extensive genomic instability starting from the early dysplastic stage and a low rate of b-catenin activation. Recurrent loss of heterozygosity at chromosomes 1, 2, 4, 5, 6, 7, 8, 9, 12, 14, 15 and X was detected in this model of liver cancer. The data indicate that similar molecular pathways described for human HCC are recapitulated in human HCC.