beta-Catenin nuclear accumulation in head and neck mucoepidermoid carcinoma: its role in cyclin D1 overexpression and tumor progression.
BACKGROUND
Nuclear/cytoplasmic accumulation of beta-catenin is mainly regulated by its degradation, which is initiated by interaction with adenomatous polyposis coli (APC) protein. Accumulation of beta-catenin activates the transcription of 1 of the target oncogenic genes, cyclin D1, in the Wnt/Wingless pathway. The role of beta-catenin and cyclin D1 in this pathway has not been previously studied in head and neck mucoepidermoid carcinoma (MEC). This study investigates abnormalities of beta-catenin and the APC gene in MEC and correlates the patterns of cyclin D1 overexpression and nuclear/cytoplasmic accumulation of beta-catenin with the clinical outcome.


METHODS
Mutations of the beta-catenin and APC genes, as well as overexpression of cyclin D1, were investigated by polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) in tissue samples from 44 cases of MEC. In addition, we employed differential PCR method to detect amplification of the cyclin D1 gene. Furthermore, the overexpression of cyclin D1 and nuclear/cytoplasmic accumulation of beta-catenin was examined by immunohistochemistry, and any correlation with clinicopathologic parameters was evaluated.


RESULTS
Nuclear/cytoplasmic accumulation of beta-catenin was observed in 6 of 44 MEC cases (13.6%), 5 of which were high-grade MEC, while the other 1 case was intermediate-grade tumor. Mutational analysis of exon 3 of the beta-catenin gene revealed that 4 of 26 cases (15.4%) contained point mutations (3 in codon 32, GAC [Asp] to GGC [Gly]; 1 in codon 42, ACA [Thr] to ATA [Ile]), and all these 4 cases showed beta-catenin accumulation immunohistochemically. The nuclear/cytoplasmic accumulation of beta-catenin was significantly correlated with the adverse outcome of patients (p = .011). Two APC gene alterations were detected in 2 cases of low-grade MEC, where there was no beta-catenin nuclear accumulation. Amplification of the cyclin D1 gene was observed in 10 of 26 cases (38.5%). Cyclin D1 overexpression was recognized in 19 of 44 cases (43.2%) and was significantly correlated with beta-catenin accumulation (p = .003).


CONCLUSIONS
These findings suggest that beta-catenin, which, in cooperation with cyclin D1, plays crucial role in the Wnt-signaling pathway, may also contribute to the adverse outcome and high-grade tumor staging of MEC.
Shiratsuchi
Hideki
H
Department of Otorhinolaryngology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. sirahide@med.kyushu-u.ac.jp
Nakashima
Torahiko
T
Hirakawa
Naoya
N
Toh
Satoshi
S
Nakagawa
Takashi
T
Saito
Tsuyoshi
T
Tsuneyoshi
Masazumi
M
Komune
Shizuo
S
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018277:Carcinoma, Mucoepidermoid / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D003062:Codon; D019938:Cyclin D1 / Q000096:biosynthesis*; D018450:Disease Progression; D005091:Exons; D005260:Female; D017491:Genes, APC; D006258:Head and Neck Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D016019:Survival Analysis; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism*
D003062:Codon; D051176:beta Catenin; D019938:Cyclin D1