Frequent beta-catenin alteration in gallbladder carcinomas.
To investigate the contribution of beta-catenin to the development of gallbladder carcinoma, genetic alteration in beta-catenin gene, ctnnb-1 and subcellular localization of beta-catenin protein were searched. Mutational analysis of exon 3 in ctnnb-1, which encodes the serine/threonine residues for GSK3beta phosphorylation sites, was performed for 21 gallbladder carcinomas affected with/without the pancreaticobiliary malunion, PBM, and 6 non-cancerous tissues affected with PBM. We also analyzed subcellular localization of beta-catenin protein in all cases immunohistochemically. Nucleotide sequencing analysis revealed that none of them carried mutations that altered amino acid residues in the potential GSK3beta phophorylation sites, but one nucleotide substitution was found. We also analyzed subcellular localization of beta-catenin protein in all cases immunohistochemically, and confirmed its accumulation in both the nucleus and cytoplasm in 10 out of 21 cancer tissues, while the non-cancerous tissues which were affected with PBM and histologically diagnosed as hyperplasia or dysplasia displayed intense membranous staining. A significant correlation between cytoplasmic or nuclear beta-catenin immunoreactivity and clinicopathological status of gallbladder carcinomas was found, especially in the poorer histological differentiation grade(p < 0.05). In conclusion our results suggested that beta-catenin alteration might be a minor contributor to the development of gallbladder carcinomas through abnormal Wnt-wingless signalling, however, decreased membranous expression of beta-catenin might be correlated to carcinoma progression through loss of cell adhesive function in E-cadherin-catenin fashion.
Kimura
Y
Y
First Dept. of Surgery, Sapporo Medical University, Sapporo, Japan.
Furuhata
T
T
Mukaiya
M
M
Kihara
C
C
Kawakami
M
M
Okita
K
K
Yanai
Y
Y
Zenbutsu
H
H
Satoh
M
M
Ichimiya
S
S
Hirata
K
K
D000328:Adult; D000368:Aged; D001665:Binding Sites; D002454:Cell Differentiation; D003598:Cytoskeletal Proteins / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005706:Gallbladder Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000235:genetics; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010766:Phosphorylation; D018807:Polymorphism, Single-Stranded Conformational; D012694:Serine / Q000737:chemistry; D015398:Signal Transduction; D013912:Threonine / Q000737:chemistry; D015534:Trans-Activators / Q000235:genetics* / Q000378:metabolism; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D015534:Trans-Activators; D051176:beta Catenin; D013912:Threonine; D012694:Serine; D004247:DNA; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3