Correlation of P-cadherin and β-catenin expression and phosphorylation with carcinogenesis in rat tongue cancer induced with 4-nitroquinoline 1-oxide

• Published in: Oral oncology 2003-07, Vol.39 (5), p.506-514
• Main Authors: TAMURA, Isao, SAKAKI, Toshio, CHAQOUR, Brahim, HOWARD, Pamela S, IKEO, Takashi, MACARAK, Edward J
• Format: Article
• Language: English
• Subjects: 4-Nitroquinoline-1-oxide; Animals; beta Catenin; Biological and medical sciences; Blotting, Western - methods; Cadherins - metabolism; Carcinogens; Cytoskeletal Proteins - metabolism; Male; Medical sciences; Neoplasm Proteins - metabolism; Otorhinolaryngology. Stomatology; Phosphorylation; Rats; Rats, Sprague-Dawley; Tongue Neoplasms - chemically induced; Tongue Neoplasms - metabolism; Trans-Activators - metabolism; Tumors; Upper respiratory tract, upper alimentary tract, paranasal sinuses, salivary glands: diseases, semeiology
• ISSN: 1368-8375; 1879-0593
• DOI: 10.1016/S1368-8375(03)00013-7

Using biochemical and immunohistochemical techniques, we have investigated P-cadherin, beta-catenin, c-src and c-met protein expression, and phosphorylation of beta-catenin in a rat model of tongue cancer induced with 4-nitroquinoline 1-oxide. Six-week-old male Sprague-Dawley rats were given either normal drinking water (controls) or 50 ppm 4NQO solution as drinking water for 16 and 20 weeks. This treatment produced dysplasia and well-differentiated squamous cell cancer in rat tongues after 16 and 20 weeks, respectively. In controls, P-cadherin and beta-catenin were expressed only in cell membranes of tongue suprabasal epithelial cells, whereas strong reaction to P-cadherin antibody was observed during carcinogenesis, especially in nests of cancer cells. However, dysplastic and cancer cells expressed beta-catenin not only in cell membranes but also in the nuclear and cytoplasmic compartments. During carcinogenesis, immunohistochemical reaction to phosphotyrosine increased gradually. Reaction to the c-src product was strongest at the dysplastic stage and, to the c-met product, at the cancer stage. In addition, western blotting analysis showed a marked increase in the expression of beta-catenin and phosphotyrosine in dysplastic and cancer cells compared with the controls. Using immunoprecipitation and western blotting techniques, we found that phosphorylated beta-catenin gradually increased during carcinogenesis. These experiments demonstrate that cell-cell adhesion in epithelial cells was reduced by phosphorylation of beta-catenin and that beta-catenin overexpression in nuclear and cytoplasmic compartments during carcinogenesis and the production of the c-met product that is associated with the phosphorylation of beta-catenin in tongue cancer.