Progression through G1-S transition and S phase of the cell cycle is mediated by
cyclin-dependent kinase 2 (cdk2), which interacts with several
cyclins. Two of these,
cyclin E and
cyclin A2 (also known as
cyclin A), are overexpressed in many
cancers.
Cyclin E2 and
cyclin A1 are recently discovered cdk2-interacting
cyclins that are found in malignant tumor cell lines and in
acute myeloid leukemia, respectively. Expression and prognostic role of these
cyclins in solid
tumors is unknown. Here, we have analyzed expression and prognostic relevance of the cdk2-associated
cyclins in
non-small cell lung cancer (NSCLC). Fresh-frozen biopsies (n = 70) from completely resected
tumors with stage I to IIIA NSCLC were studied. Gene expression was analyzed by quantitative real-time reverse transcription-PCR. Expression levels of
cyclin E (P = 0.04) and
cyclin A2 (P = 0.004) were significantly higher in the
tumor samples than in normal controls.
Cyclin A1,
cyclin A2, and
cyclin E2 expression levels did not have prognostic relevance for survival. The mean survival time associated with low and high levels of
cyclin E was 69.4 and 47.2 months, respectively, which was statistically significant (P = 0.03). Differences in survival were particularly pronounced in stages I and II.
Cyclin E was also closely associated with the development of distant
metastasis (P = 0.01). Finally, we confirmed by immunohistochemistry analyses that
cyclin E mRNA expression was closely associated with
cyclin E protein expression. In conclusion,
cyclin E is a strong independent prognostic
indicator in patients with early-stage NSCLC, whereas
cyclin E2,
cyclin A1, and
cyclin A2 do not have a prognostic role in NSCLC.