Expression of
cyclins A and E and
cyclin-dependent kinase 2 (CDK2) was examined immunohistochemically in 190 cases of human lung
carcinoma.
Cyclin A and CDK2 were expressed in the majority of
squamous cell carcinomas,
small cell carcinomas, and
large cell carcinomas, but in significantly fewer cases of
adenocarcinomas.
Cyclin E was expressed in a minority of all subtypes. In particular, well differentiated cells in
squamous cell carcinoma stained positively for
cyclin E; in contrast,
cyclin A was expressed in the nonkeratinized proliferating areas of the
tumor nests. Immunoblotting revealed that all these
proteins were expressed at higher levels in
tumor tissues than in adjacent normal tissues. Immunoprecipitation also revealed higher levels of
cyclin A and
cyclin E associated with CDK2 in
tumor tissues. Furthermore,
tumor tissues which exhibited higher
cyclin A and CDK2 expression also had higher CDK2
kinase activity. However,
cyclin E-associated
kinase activity was barely detectable even in
tumor samples exhibiting higher
cyclin E expression. Consistent with these data, elevated expression of
cyclin A correlated to shorter survival periods in contrast to expression of
cyclin E, which correlated to longer survival periods. These results suggest that in human lung
carcinomas, elevated expression of active
cyclin A-CDK2 complexes with associated higher CDK2
kinase activity is critical for promoting cell cycle progression and unrestrained proliferation of
tumor cells and can be a predictive marker for patients' prognosis. On the other hand, immunohistochemical detection of
cyclin E-CDK2 reflects accumulation of inactive forms of
protein complexes, implying differentiation or senescence of the
tumor and the better prognosis.