Immunohistochemical and mutational analyses of Wnt signaling components and target genes in intrahepatic cholangiocarcinomas.
The mechanisms of carcinogenesis in intrahepatic cholangiocarcinoma (ICC) are not well characterized although alterations in several oncogenes and onco-suppressor genes have been reported to occur in ICC. In the present study, we focused on alterations in the Wnt signaling components and target genes by analyzing 24 surgically resected samples of ICC. Immunohistochemical analysis of beta-catenin showed positive staining in cytoplasm and/or nucleus in 58.3% of the samples, indicating the presence of alterations in the Wnt signaling pathway in these samples. In sequencing analyses, mutations in the beta-catenin, adenomatous polyposis coli and Axin 1 genes were observed in 8.3, 12.5 and 41.7%, respectively, of the 24 ICC samples; however, the functional significance of these mutated genes is controversial. Furthermore, cyclin D1, c-myc and urinary-type plasminogen activator receptor, which are the downstream target genes in the Wnt signaling pathway, were overexpressed in 41.7, 41.7 and 58.3%, respectively, of the 24 ICC samples. The overexpression of cyclin D1 was statistically correlated with that of beta-catenin. Based on these results, we speculated that the Wnt signaling pathway plays an important role in carcinogenesis in ICC through overexpression of its target genes, particularly cyclin D1.
Tokumoto
Noriaki
N
Department of Surgery, Division of Frontier Medical Science, Programs for Biomedical Research, Graduate School of Biomedical Sciences, Hiroshima University, Hiroshima, Japan.
Ikeda
Satoshi
S
Ishizaki
Yasuyo
Y
Kurihara
Takeshi
T
Ozaki
Shinji
S
Iseki
Masahiko
M
Shimizu
Yosuke
Y
Itamoto
Toshiyuki
T
Arihiro
Koji
K
Okajima
Masazumi
M
Asahara
Toshimasa
T
D000368:Aged; D000818:Animals; D060466:Axin Protein; D002467:Cell Nucleus / Q000378:metabolism; D018281:Cholangiocarcinoma / Q000235:genetics* / Q000378:metabolism*; D019938:Cyclin D1 / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000235:genetics* / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D009154:Mutation; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D055293:Receptors, Urokinase Plasminogen Activator; D012097:Repressor Proteins / Q000378:metabolism; D017422:Sequence Analysis, DNA; D015398:Signal Transduction; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism
C555451:AXIN1 protein, human; D060466:Axin Protein; C524898:PLAUR protein, human; D016271:Proto-Oncogene Proteins c-myc; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D012097:Repressor Proteins; D051153:Wnt Proteins; D051176:beta Catenin; D019938:Cyclin D1; D014568:Urokinase-Type Plasminogen Activator