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Overexpression of Cyclin A but not Skp 2 Correlates with the Tumor Relapse of Human Hepatocellular Carcinoma¹

Division of Gastroenterology, Department of Internal Medicine [Y. C., S-D. L.], and Department of Surgery [J-H. C., G-Y. C., W-Y. L.], Veterans General Hospital-Taipei; Cooperative Laboratory, Cancer Research Division, National Health Research Institutes [Y-L. S., W. K. Y., T-S. H.]; and Institute of Clinical Medicine, National Yang-Ming University [Y. C.], Taipei 112, Taiwan, Republic of China

Cyclin A is an S- and G₂-M-phase regulatory protein, and its abnormal expression has been implicated in cellular transformation. This work was undertaken to investigate the frequency of cyclin A overexpression and the correlated clinical outcome in human hepatocellular carcinoma (HCC). Herein, 12 of 31 (39%) patients exhibited cyclin A overexpression in their tumorous tissues, resulting from gene amplification in 6 of 12 patients, (post)transcription in 4 of 12 patients, and (post)translation in 2 of 12 patients. Patients who overexpressed cyclin A had significantly more tumor cells in the S and G₂-M phases compared with those expressing a normal cyclin A level (P = 0.007 and 0.039, respectively). 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 to have more S-phase tumor cells (P = 0.07). By an unpaired Student's t test and a Fisher's exact or x² analysis, overexpression of cyclin A had a strong correlation with elevated Skp 2 expression and increased -fetoprotein levels (P = 0.001 and 0.009, respectively), but it was not associated with patients' age, tumor size, cirrhosis, or the positive detection of hepatitis B virus surface antigen. In the disease-free survival analysis, patients whose tumors overexpressed cyclin A had a median disease-free survival of 6 months, whereas patients who lacked cyclin A overexpression exhibited a longer median period of 29 months (P = 0.046). The overall survival analysis revealed the same trend, i.e., cyclin A-overexpressing patients had shorter overall survival periods (median, 12 versus 50 months; P = 0.09). By multivariate analysis, the correlation of cyclin A overexpression with shorter disease-free periods remained significant after adjustment for Skp 2 overexpression and -fetoprotein induction (P = 0.019). These data suggest that overexpression of cyclin A can be an independent prognostic factor for the tumor relapse of human HCC.

¹ This work was partly supported by Grant NSC 86-2314-B-075-051 from the National Science Council of the Republic of China.

² To whom requests for reprints should be addressed, at Cooperative Laboratory, Veterans General Hospital-Taipei, Cancer Research Division, National Health Research Institutes, 201, Sec 2, Shih-Pai Road, Taipei 112, Taiwan, Republic of China. Fax: 886-2-28733664; E-mail: tshuang@nhri.org.tw.

Received 8/11/97. Accepted 12/31/97.

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