Loss of beta-catenin expression in metastatic gastric cancer.
OBJECTIVE
Beta-catenin (beta-catenin) participates in intercellular adhesion and is an integral part of the Wnt signaling pathway. The role of beta-catenin in the pathogenesis of gastric cancer and its metastasis is largely unknown.


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


RESULTS
beta-Catenin expression was present at either the cell membrane or the cytoplasm in 34 of 75 primary gastric cancers. Expression of beta-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 beta-catenin protein. N87 cells, derived from the liver metastasis of a gastric cancer, did not express beta-catenin. Treatment with 5'-azadeoxycytidine restored beta-catenin protein levels in this cell line, which exhibited significantly more 5-methylcytosines in the beta-catenin promoter compared with the other cell lines.


CONCLUSIONS
beta-Catenin expression is lost in a subgroup of primary gastric cancers, is frequently absent in metastases, and exhibits nuclear localization in cancers with either beta-catenin or APC gene mutations. Interestingly, the loss of beta-catenin expression in metastatic gastric cancers may result from hypermethylation of the beta-catenin promoter.
Ebert
Matthias P A
MP
Otto-von-Guericke University, Department of Gastroenterology, Hepatology, and Infectious Diseases, Leipzigerstr 44, D-39120 Magdeburg, Germany. Matthias.Ebert@medizin.uni-magdeburg.de
Yu
Jun
J
Hoffmann
Juliane
J
Rocco
Alba
A
Röcken
Christoph
C
Kahmann
Sabine
S
Müller
Oliver
O
Korc
Murray
M
Sung
Joseph J
JJ
Malfertheiner
Peter
P
D011125:Adenomatous Polyposis Coli / Q000235:genetics*; D000328:Adult; D000368:Aged; D015153:Blotting, Western; D015820:Cadherins; D002462:Cell Membrane; D003593:Cytoplasm; D003598:Cytoskeletal Proteins / Q000096:biosynthesis* / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017491:Genes, APC; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis / Q000235:genetics*; D011401:Promoter Regions, Genetic; D013274:Stomach Neoplasms / Q000235:genetics* / Q000473:pathology*; D015534:Trans-Activators / Q000096:biosynthesis* / Q000235:genetics; D014407:Tumor Cells, Cultured; D051176:beta Catenin
C495270:CTNNB1 protein, human; D015820:Cadherins; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin