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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
Author(s) -
Prange Wilhelm,
Breuhahn Kai,
Fischer Frank,
Zilkens Christoph,
Pietsch Torsten,
Petmecky Katharina,
Eilers Renate,
Dienes HansPeter,
Schirmacher Peter
Publication year - 2003
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.1448
Subject(s) - hccs , catenin , beta catenin , cyclin d1 , wnt signaling pathway , cadherin , biology , cancer research , nuclear localization sequence , cyclin d , gene expression , microbiology and biotechnology , gene , cell cycle , hepatocellular carcinoma , genetics , cell
Abstract Beta‐catenin integrates intracellular WNT signalling and the intercellular E‐cadherin–catenin adhesion system. To date, little is known about the role of β‐catenin activation and nuclear accumulation in hepatocarcinogenesis. This study has analysed β‐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 β‐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 β‐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 β‐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 β‐catenin, proliferation, or grading. Sequence analysis of the β‐catenin gene revealed no detectable mutations in DNs, but mutations in the GSK‐3β binding site were present in 14.3% of the HCCs. In conclusion, this study has demonstrated that nuclear accumulation of β‐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 β‐catenin in human HCC differs significantly from its established function in colon carcinogenesis. Copyright © 2003 John Wiley & Sons, Ltd.