EXPRESSION OF G1-]S TRANSITION REGULATORY MOLECULES IN HUMAN UROTHELIAL CANCER

Growth of cancer cells is characterized by accelerated passage through the cell cycle, which is often caused by deregulation of the G1-->S t ransition. In this study the expression of G1-->S transition regulator y molecules was analyzed in 32 transitional cell carcinoma specimens a nd fifteen normal tissues obtained by cystectomy or nephroureterectomy of mainly locally advanced tumors, as well as six bladder cancer cell lines. Expression of mRNAs for cyclins D1 and D2 and cyclin-dependent kinases (CDK) 2 and 4 was investigated by quantitative reverse transc ription-polymerase chain reaction, Overexpression of cyclin D1 compare d to normal mucosa was observed in 3 tumors (9.4%), but in neither of the cell lines. All tumors with overexpression were moderately differe ntiated (G2) pT1 or pT2 tumors, and thus among the less advanced speci mens, Cyclin D2 was not expressed in normal bladder mucosa or in tumor s. The expression of CDK4 mRNA varied within the same range in mucosa, tumors, and cell lines, CDK2 mRNA expression varied more strongly and was diminished in individual tumors and in four cell lines, It is con cluded that cyclin D1 overexpression can play an important role in the early stage of urothelial tumorigenesis, driving cell proliferation. Ectopic expression of cyclin D2 or amplification of CDK4 does not occu r at a significant frequency in urothelial carcinomas. Different expre ssion patterns of cyclin D1 and CDK2 indicate heterogeneity in the mec hanisms of G1-->S transition deregulation in individual bladder tumors which may elicit differences in their biological and clinical behavio r.