OVEREXPRESSION OF CYCLIN-A BUT NOT SKP-2 CORRELATES WITH THE TUMOR RELAPSE OF HUMAN HEPATOCELLULAR-CARCINOMA

Cyclin A is an S- and G(2)-M-phase regulatory protein, and its abnorma l expression has been implicated in cellular transformation, This work was undertaken to investigate the frequency of cyclin A overexpressio n and the correlated clinical outcome in human hepatocellular carcinom a (HCC), Herein, 12 of 31 (39%) patients exhibited cyclin A overexpres sion in their tumorous tissues, resulting from gene amplification in 6 of 12 patients, (post)transcription in 4 of 12 patients, and (post)tr anslation in 2 of 12 patients, Patients who overexpressed cyclin A had significantly more tumor cells in the S and G(2)-M phases compared wi th those expressing a normal cyclin A level (P = 0.007 and 0.039, resp ectively), Increased levels of Skp 2, a cyclin A-interacting protein, were also found in 17 of 31 (55%) of HCC patients who showed a trend t o have more S-phase tumor cells (P = 0.07), By an unpaired Student's t test and a Fisher's exact or chi(2) analysis, overexpression of cycli n A had a strong correlation with elevated Skp 2 expression and increa sed alpha-fetoprotein levels (P = 0.001 and 0.009, respectively), but it was not associated with patients' age, tumor size, cirrhosis, or th e positive detection of hepatitis B virus surface antigen, In the dise ase-free survival analysis, patients whose tumors overexpressed cyclin A had a median disease-free survival of 6 months, whereas patients wh o lacked cyclin A overexpression exhibited a longer median period of 2 9 months (P = 0.046), The overall survival analysis revealed the same trend, i.e., cyclin A-overexpressing patients had shorter overall surv ival periods (median, 12 versus 50 months; P = 0.09), By multivariate analysis, the correlation of cyclin A overexpression with shorter dise ase-free periods remained significant after adjustment for Skp 2 overe xpression and cu-fetoprotein induction (P = 0.019), These data suggest that overexpression of cyclin A can be an independent prognostic fact or for the tumor relapse of human HCC.