Prange Wilhelm, Breuhahn Kai, Fischer Frank, Zilkens Christoph, Pietsch Torsten, Petmecky Katharina, Eilers Renate, Dienes Hans-Peter, Schirmacher Peter
Institute of Pathology, University of Cologne, D-50931 Cologne, Germany.
J Pathol. 2003 Oct;201(2):250-9. doi: 10.1002/path.1448.
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, MMP-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.
β-连环蛋白整合细胞内WNT信号传导和细胞间E-钙黏蛋白-连环蛋白黏附系统。迄今为止，关于β-连环蛋白激活和核积累在肝癌发生中的作用知之甚少。本研究分析了人类发育异常结节（DN）以及肝细胞癌（HCC）中β-连环蛋白的表达模式，并与增殖、WNT-1靶基因表达、E-钙黏蛋白和p53进行了比较。根据既定标准对170例HCC和25例DN进行分类，并分析β-连环蛋白的表达模式。对一组代表性病例进行增殖活性分析以及E-钙黏蛋白、细胞周期蛋白D1、基质金属蛋白酶-7（MMP-7）、c-myc和p53表达分析。所有DN均无核β-连环蛋白，而所有HCC中有36%呈阳性，核染色细胞数量从不到1%至超过90%不等。β-连环蛋白核积累增加与膜性E-钙黏蛋白表达降低和核p53相关，但与增殖无关。细胞周期蛋白D1、MMP-7和c-myc表达分别在54%、26%和65%的HCC中检测到，但与核β-连环蛋白、增殖或分级无关。β-连环蛋白基因序列分析显示DN中未检测到突变，但14.3%的HCC中存在糖原合成酶激酶-3β（GSK-3β）结合位点突变。总之，本研究表明β-连环蛋白核积累是人类肝癌发生中常见的进展事件，与核p53积累和膜性E-钙黏蛋白丧失相关，但与既定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已确定的功能有显著差异。
