ALTERED EXPRESSION OF CYCLIN D1 AND CYCLIN-DEPENDENT KINASE-4 IN AZOXYMETHANE-INDUCED MOUSE COLON TUMORIGENESIS

Alterations in the expression of the cell cycle regulators, cyclin D1 and cyclin-dependent kinase 4 (Cdk4), have been implicated in malignan cies of both humans and experimental animal models, We hypothesize tha t altered expression of cyclin D1 and Cdk4 may also be involved in mou se colon tumorigenesis induced by the chemical carcinogen, azoxymethan e (AOM), In the present study, SWR/J mice were given AOM by i.p. injec tion at a dose of 10 mg/kg once a week for 8 weeks, and colonic tissue and tumors were isolated 18 weeks later. The expression and localizat ion of cyclin D1 and Cdk4 were examined by reverse transcription-polym erase chain reaction (RT-PCR) and immunohistochemical analyses. Cyclin D1 and Cdk4 mRNA levels in tumor samples were increased 1.3-fold (P < 0.01) and 1.2-fold (P < 0.01), respectively, when compared with contr ol mouse colon tissue. Control colon epithelium was uniformly negative for cyclin D1 immunoreactivity, whereas minimal Cdk4 nuclear staining was confined to the lower portion of the crypts within the control ti ssue. Both cyclin D1 and Cdk4 immunoreactive cells were markedly incre ased in preneoplastic lesions and in adenomas isolated from AOM-treate d mice. Furthermore, some morphologically normal colon crypts from AOM -treated mice showed positive cyclin D1 immunoreactivity. These findin gs suggest that overexpression of cyclin D1 and Cdk4 occurs early in t he AOM-induced mouse colon tumorigenesis and may contribute to tumor p rogression in this model.