Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes
Beta-catenin accumulation in the progression of human hepatocarcinogenesis correlates with loss of E-cadherin and accumulation of p53, but not with expression of conventional WNT-1 target genes
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DOI：
10.1002/path.1448
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发表时间：
2003-10-01
影响因子：
7.3
通讯作者：
Schirmacher, P
中科院分区：
文献类型：
--
作者：
Prange, W;Breuhahn, K;Schirmacher, P
β-连环蛋白整合细胞内WNT信号传导和细胞间E-钙粘蛋白-连环蛋白粘附系统。迄今为止，对β-连环蛋白激活和细胞核积聚在肝癌发生中的作用知之甚少。本研究分析了β-连环蛋白在人类异型增生结节（DN），以及在肝细胞癌（HCC）的增殖，表达WNT-1靶基因，E-钙粘蛋白，和p53的比较表达模式。170例HCC和25例DN根据已建立的标准进行分类，并分析β-连环蛋白的表达模式。对具有代表性的病例亚组进行增殖活性和E-cadherin、cyclin D1、MMP-7、c-myc和p53表达的分析。所有DN都缺乏细胞核β-连环蛋白，而所有HCC中有36%为阳性，细胞核染色细胞的数量从不到1%到超过90%不等。增加β-连环蛋白的核积累与减少膜E-钙粘蛋白表达和核p53相关，但与增殖无关。细胞周期蛋白D1、NINIP-7和c-myc的表达分别在54%、26%和65%的HCC中检测到，但与细胞核β-连环蛋白、增殖或分级无关。β-catenin基因的序列分析显示DN中没有检测到突变，但GSK-3 β结合位点的突变存在于14.3%的HCC中。总之，这项研究表明，β-连环蛋白的核积累是人类肝癌发生过程中的常见进展事件，与核p53积累和膜E-钙粘蛋白的丢失相关，但与已建立的WNT-1靶基因的表达模式无关。据推测，β-连环蛋白在人类HCC中的作用与其在结肠癌发生中的既定功能显著不同。版权所有（C）2003约翰威利父子有限公司。
Beta-catenin integrates intracellular WNT signalling and the intercellular E-cadherin-catenin adhesion system. To date, little is known about the role of beta-catenin activation and nuclear accumulation in hepatocarcinogenesis. This study has analysed beta-catenin expression patterns in human dysplastic nodules (DNs), as well as in hepatocellular carcinomas (HCCs) in comparison with proliferation, expression of WNT-1 target genes, E-cadherin, and p53. One hundred and seventy HCCs and 25 DNs were categorized according to established criteria and analysed for the expression pattern of beta-catenin. Analysis of the proliferative activity and expression of E-cadherin, cyclin D1, MMP-7, c-myc, and p53 was performed on a representative subgroup of cases. All DNs lacked nuclear beta-catenin, while 36% of all HCCs were positive, with the number of nuclear stained cells ranging from less than 1% to more than 90%. Increasing nuclear accumulation of beta-catenin correlated with reduced membranous E-cadherin expression and nuclear p53 but not with proliferation. Cyclin D1, NINIP-7, and c-myc expression was detected in 54%, 26%, and 65% of HCCs, respectively, but did not correlate with nuclear beta-catenin, proliferation, or grading. Sequence analysis of the beta-catenin gene revealed no detectable mutations in DNs, but mutations in the GSK-3beta binding site were present in 14.3% of the HCCs. In conclusion, this study has demonstrated that nuclear accumulation of beta-catenin is a frequent progression event in human hepatocarcinogenesis which correlates with nuclear p53 accumulation and loss of membranous E-cadherin, but not with the expression pattern of established WNT-1 target genes. It is hypothesized that the role of beta-catenin in human HCC differs significantly from its established function in colon carcinogenesis. Copyright (C) 2003 John Wiley Sons, Ltd.