β-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: Adult; Aged; Aged, 80 and over; APC; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Carcinoma, Mucoepidermoid - metabolism; Carcinoma, Mucoepidermoid - mortality; Carcinoma, Mucoepidermoid - pathology; Codon; cyclin D1; Cyclin D1 - biosynthesis; Disease Progression; Exons; Female; Genes, APC; Head and Neck Neoplasms - metabolism; Head and Neck Neoplasms - mortality; Head and Neck Neoplasms - pathology; Humans; Immunohistochemistry; Male; Medical sciences; Middle Aged; mucoepidermoid carcinoma; mutation; Otorhinolaryngology. Stomatology; Point Mutation; Polymerase Chain Reaction; Polymorphism, Single-Stranded Conformational; Survival Analysis; β-catenin
• ISSN: 1043-3074; 1097-0347
• DOI: 10.1002/hed.20583

Background. Nuclear/cytoplasmic accumulation of β‐catenin is mainly regulated by its degradation, which is initiated by interaction with adenomatous polyposis coli (APC) protein. Accumulation of β‐catenin activates the transcription of 1 of the target oncogenic genes, cyclin D1, in the Wnt/Wingless pathway. The role of β‐catenin and cyclin D1 in this pathway has not been previously studied in head and neck mucoepidermoid carcinoma (MEC). This study investigates abnormalities of β‐catenin and the APC gene in MEC and correlates the patterns of cyclin D1 overexpression and nuclear/cytoplasmic accumulation of β‐catenin with the clinical outcome. Methods. Mutations of the β‐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 β‐catenin was examined by immunohistochemistry, and any correlation with clinicopathologic parameters was evaluated. Results. Nuclear/cytoplasmic accumulation of β‐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 β‐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 β‐catenin accumulation immunohistochemically. The nuclear/cytoplasmic accumulation of β‐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 β‐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 β‐catenin accumulation (p = .003). Conclusions. These findings suggest that β‐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. © 2007 Wiley Periodicals, Inc. Head Neck, 2007