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Loss of Beta-Catenin Expression in Metastatic Gastric Cancer

Matthias P.A. Ebert, Jun Yu, Juliane Hoffmann, Alba Rocco, Christoph Röcken, Sabine Kahmann, Oliver Müller, Murray Korc, Joseph J. Sung, Peter Malfertheiner

From the Department of Gastroenterology, Hepatology, and Infectious Diseases and Institute of Pathology, Otto-von-Guericke University, Magdeburg; Max-Planck-Institute for Molecular Physiology, Dortmund, Germany; Department of Medicine and Therapeutics, Prince of Wales Hospital, Chinese University of Hong Kong, Hong Kong; and Division of Endocrinology, Diabetes and Metabolism, University of California, Irvine, CA.

Address reprint requests to Matthias Ebert, MD, Otto-von-Guericke University, Department of Gastroenterology, Hepatology, and Infectious Diseases, Leipzigerstr 44, D-39120 Magdeburg, Germany; email: Matthias.Ebert{at}medizin.uni-magdeburg.de.

Purpose: Beta-catenin (ß-catenin) participates in intercellular adhesion and is an integral part of the Wnt signaling pathway. The role of ß-catenin in the pathogenesis of gastric cancer and its metastasis is largely unknown.

Patients and Methods: Immunohistochemistry and Western blot analysis were used to analyze the expression of ß-catenin in 87 human gastric cancers, in metastasis and cancer cell lines. The ß-catenin and the adenomatous polyposis coli (APC) genes were analyzed for gene mutations. Furthermore, methylation of the ß-catenin promoter in cell lines was assessed by treatment with 5'-azadeoxycytidine and sodium bisulfite genomic sequencing.

Results: ß-Catenin expression was present at either the cell membrane or the cytoplasm in 34 of 75 primary gastric cancers. Expression of ß-catenin was significantly more frequent in intestinal-type (P = .0049) and well-differentiated gastric cancers (P < .001). There were no quantitative differences between gastric cancers and the nonmalignant gastric tissues, as determined by Western blot analysis. One of 18 metastatic cancer lesions and four of five gastric cancer cell lines expressed ß-catenin protein. N87 cells, derived from the liver metastasis of a gastric cancer, did not express ß-catenin. Treatment with 5'-azadeoxycytidine restored ß-catenin protein levels in this cell line, which exhibited significantly more 5-methylcytosines in the ß-catenin promoter compared with the other cell lines.

Conclusion: ß-Catenin expression is lost in a subgroup of primary gastric cancers, is frequently absent in metastases, and exhibits nuclear localization in cancers with either ß-catenin or APC gene mutations. Interestingly, the loss of ß-catenin expression in metastatic gastric cancers may result from hypermethylation of the ß-catenin promoter.

M.P.A.E. is supported by the Heisenberg-Programm and a grant from the Deutsche Forschungsgemeinschaft (Eb 187/4-1; Eb 187/5-1).

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