b-Catenin nuclear accumulation in head and neck mucoepidermoid carcinoma: Its role in cyclin D1 overexpression and tumor progression

• Published in: Head & neck 2007-06, Vol.29 (6), p.577-584
• Main Authors: Shiratsuchi, Hideki, Nakashima, Torahiko, Hirakawa, Naoya, Toh, Satoshi, Nakagawa, Takashi, Saito, Tsuyoshi, Tsuneyoshi, Masazumi, Komune, Shizuo
• Format: Article
• Language: English
• Subjects: adenomatous polyposis coli; adenomatous polyposis coli protein; Carcinoma; catenin; Codons; Cooperation; cyclin D1; Exons; Head; Immunohistochemistry; Neck; Point mutation; Polymerase chain reaction; Single strand conformation polymorphism; Transcription; Tumors; Wnt protein
• ISSN: 1043-3074
• DOI: 10.1002/hed.20583

Background. Nuclear/cytoplasmic accumulation of -catenin is mainly regulated by its degradation, which is initiated by interaction with adenomatous polyposis coli (APC) protein. Accumulation of -catenin activates the transcription of 1 of the target oncogenic genes, cyclin D1, in the Wnt/Wingless pathway. The role of -catenin and cyclin D1 in this pathway has not been previously studied in head and neck mucoepidermoid carcinoma (MEC). This study investigates abnormalities of -catenin and the APC gene in MEC and correlates the patterns of cyclin D1 overexpression and nuclear/cytoplasmic accumulation of -catenin with the clinical outcome. Methods. Mutations of the -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 -catenin was examined by immunohistochemistry, and any correlation with clinicopathologic parameters was evaluated. Results. Nuclear/cytoplasmic accumulation of -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 -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 -catenin accumulation immunohistochemically. The nuclear/cytoplasmic accumulation of -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 -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 -catenin accumulation (p = .003). Conclusions. These findings suggest that -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.