Correlation of P-cadherin and beta-catenin expression and phosphorylation with carcinogenesis in rat tongue cancer induced with 4-nitroquinoline 1-oxide.
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.
Tamura
Isao
I
Department of Biochemistry, Osaka Dental University, Hirakata-shi, Osaka, Japan. tamura@cc.osaka-dent.ac.jp
Sakaki
Toshio
T
Chaqour
Brahim
B
Howard
Pamela S
PS
Ikeo
Takashi
T
Macarak
Edward J
EJ
D015112:4-Nitroquinoline-1-oxide; D000818:Animals; D015153:Blotting, Western / Q000379:methods; D015820:Cadherins / Q000378:metabolism*; D002273:Carcinogens; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D008297:Male; D009363:Neoplasm Proteins / Q000378:metabolism*; D010766:Phosphorylation; D051381:Rats; D017207:Rats, Sprague-Dawley; D014062:Tongue Neoplasms / Q000139:chemically induced / Q000378:metabolism*; D015534:Trans-Activators / Q000378:metabolism*; D051176:beta Catenin
D015820:Cadherins; D002273:Carcinogens; C495268:Ctnnb1 protein, rat; D003598:Cytoskeletal Proteins; D009363:Neoplasm Proteins; D015534:Trans-Activators; D051176:beta Catenin; D015112:4-Nitroquinoline-1-oxide