Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas.
OBJECTIVE
CDC25 genes are cell cycle-activating phosphatases that positively regulate the activity of cyclin-dependent kinase. CDC25A and CDC25B, being oncogenes, are overexpressed in a variety of human malignancies. To investigate the potential roles of CDC25s in hepatocellular carcinoma (HCC), expression of CDC25A and CDC25B was examined in human HCC samples.


RESULTS
Reverse transcription-PCR showed that overexpression of CDC25A and CDC25B mRNAs was found in 9 of 13 (69%) and 4 of 13 (31%) HCCs, respectively. Immunohistochemistry of 59 HCCs showed marked increase in CDC25A expression, but not CDC25B, in HCC compared with noncancer tissues, and high expression of CDC25A in 33 of 59 (56%) HCCs. Overexpression of CDC25A in HCC was confirmed by Western blot analysis. High expression of CDC25A was associated with dedifferentiated phenotype and portal vein invasion (P = 0.001 and 0.031, respectively), and expression of CDC25A correlated well with proliferating cell nuclear antigen labeling index (P = 0.005). Univariate analysis indicated that high expression of CDC25A and proliferating cell nuclear antigen were both significant predictive factors for shorter disease-free survival (P = 0.004 and 0.039, respectively). Multivariate analysis indicated that CDC25A was an independent prognostic marker for disease-free survival (risk ratio for cancer relapse, 2.98; P = 0.029), even when analyzed with several clinicopathologic factors. On the other hand, expression of CDC25B did not correlate with any clinicopathological features.


CONCLUSIONS
Our findings suggest that CDC25A, but not CDC25B, could be used as an independent prognostic marker for HCC. Our data would also contribute to forward understanding of tumor biology of HCC that is associated with cell cycle regulation.
Xu
Xundi
X
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, Japan.
Yamamoto
Hirofumi
H
Sakon
Masato
M
Yasui
Masayoshi
M
Ngan
Chew Yee
CY
Fukunaga
Hiroki
H
Morita
Tetsushi
T
Ogawa
Minoru
M
Nagano
Hiroaki
H
Nakamori
Shoji
S
Sekimoto
Mitsugu
M
Matsuura
Nariaki
N
Monden
Morito
M
D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000096:biosynthesis; D015153:Blotting, Western; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000201:enzymology* / Q000401:mortality; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism; D002455:Cell Division; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000175:diagnosis / Q000201:enzymology* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011379:Prognosis; D018809:Proliferating Cell Nuclear Antigen / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012334:RNA, Neoplasm / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015996:Survival Rate; D020687:cdc25 Phosphatases / Q000235:genetics / Q000378:metabolism*
D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; D018809:Proliferating Cell Nuclear Antigen; D012333:RNA, Messenger; D012334:RNA, Neoplasm; C517004:CDC25A protein, human; C517008:CDC25B protein, human; D020687:cdc25 Phosphatases