Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas.

PURPOSE AND EXPERIMENTAL DESIGN 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. CONCLUSION 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.

[1]  M. Kojiro,et al.  Relationship of histologic grade of hepatocellular carcinoma (HCC) to tumor size, and demonstration of tumor cells of multiple different grades in single small HCC. , 2008, Liver.

[2]  C. Wilcox,et al.  Involvement of Cdc25A phosphatase in Hep3B hepatoma cell growth inhibition induced by novel K vitamin analogs. , 2001, Cancer research.

[3]  Y. Doki,et al.  Clinical significance of CDC25A and CDC25B expression in squamous cell carcinomas of the oesophagus , 2001, British Journal of Cancer.

[4]  C. Cerni,et al.  Cdc25A phosphatase suppresses apoptosis induced by serum deprivation , 2001, Oncogene.

[5]  H. Kiyokawa,et al.  The Cell Cycle-Regulatory CDC25A Phosphatase Inhibits Apoptosis Signal-Regulating Kinase 1 , 2001, Molecular and Cellular Biology.

[6]  G. Ercolani,et al.  Improved Results of Liver Resection for Hepatocellular Carcinoma on Cirrhosis Give the Procedure Added Value , 2001, Annals of surgery.

[7]  N. Nagasue,et al.  Prognostic factors and survival after hepatic resection for hepatocellular carcinoma without cirrhosis , 2001, The British journal of surgery.

[8]  G. Powis,et al.  Syntheses and biological activities of a novel group of steroidal derived inhibitors for human Cdc25A protein phosphatase. , 2001, Journal of medicinal chemistry.

[9]  J. Slingerland,et al.  Reduction of Cdc25A contributes to cyclin E1-Cdk2 inhibition at senescence in human mammary epithelial cells , 2000, Oncogene.

[10]  V Torri,et al.  Cell cycle-related phosphatases CDC25A and B expression correlates with survival in ovarian cancer patients. , 2000, Anticancer research.

[11]  M. Loda,et al.  Role of the Cdc25A phosphatase in human breast cancer. , 2000, The Journal of clinical investigation.

[12]  H. Naiki,et al.  Prognostic significance of proliferative activity in pN2 non-small-cell lung carcinomas and their mediastinal lymph node metastases. , 2000, Annals of surgery.

[13]  M Monden,et al.  Overexpression of CDC25B phosphatase as a novel marker of poor prognosis of human colorectal carcinoma. , 2000, Cancer research.

[14]  H. Hibshoosh,et al.  Increased susceptibility to carcinogen-induced mammary tumors in MMTV-Cdc25B transgenic mice , 1999, Oncogene.

[15]  Ingrid,et al.  Ectopic Expression of Cdc25A Accelerates the G1/S Transition and Leads to Premature Activation of Cyclin E- and Cyclin A-Dependent Kinases , 1999, Molecular and Cellular Biology.

[16]  S. Tsai,et al.  Induction of mammary gland hyperplasia in transgenic mice over-expressing human Cdc25B , 1999, Oncogene.

[17]  M. Monden,et al.  Expression and prognostic roles of the G1‐S modulators in hepatocellular carcinoma: p27 independently predicts the recurrence , 1999, Hepatology.

[18]  R. Prywes,et al.  Serum-Induced Expression of the cdc25AGene by Relief of E2F-Mediated Repression , 1999, Molecular and Cellular Biology.

[19]  L. Mao,et al.  Overexpression of cdc25A and cdc25B is frequent in primary non-small cell lung cancer but is not associated with overexpression of c-myc. , 1998, Cancer research.

[20]  M. Buendia,et al.  Somatic mutations of the beta-catenin gene are frequent in mouse and human hepatocellular carcinomas. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[21]  T. Moyana,et al.  Elevated expression of the cdc25A protein phosphatase in colon cancer. , 1998, Experimental cell research.

[22]  E. Montserrat,et al.  cdc25 cell cycle-activating phosphatases and c-myc expression in human non-Hodgkin's lymphomas. , 1998, Cancer Research.

[23]  Jeng-Jong Hwang,et al.  Ki‐67 expression as a prognostic marker in patients with hepatocellular carcinoma , 1998, Journal of gastroenterology and hepatology.

[24]  H. Yokozaki,et al.  Overexpression of Cyclin‐dependent Kinase‐activating CDC25B Phosphatase in Human Gastric Carcinomas , 1997, Japanese journal of cancer research : Gann.

[25]  Xiao-Feng Sun,et al.  Ki‐67 expression in relation to clinicopathological variables and prognosis in colorectal adenocarcinomas , 1997, APMIS : acta pathologica, microbiologica, et immunologica Scandinavica.

[26]  R. Maestro,et al.  Overexpression of CDC25A and CDC25B in head and neck cancers. , 1997, Cancer research.

[27]  J. Massagué,et al.  Repression of the CDK activator Cdc25A and cell-cycle arrest by cytokine TGF-β in cells lacking the CDK inhibitor p15 , 1997, Nature.

[28]  S. Hirohashi,et al.  Reduced p21WAF1/CIP1 expression and p53 mutation in hepatocellular carcinomas , 1997, Hepatology.

[29]  D. Huhn,et al.  Quantification of Bcr-Abl transcripts in chronic myelogenous leukemia (CML) using standardized, internally controlled, competitive differential PCR (CD-PCR). , 1996, Nucleic acids research.

[30]  S. Hirohashi,et al.  Inactivation of p16INK4 in hepatocellular carcinoma , 1996, Hepatology.

[31]  D. Beach,et al.  Cdc25 cell-cycle phosphatase as a target of c-myc , 1996, Nature.

[32]  N. Hayward,et al.  Cytoplasmic accumulation of cdc25B phosphatase in mitosis triggers centrosomal microtubule nucleation in HeLa cells. , 1996, Journal of cell science.

[33]  O. Nakashima,et al.  Pathology of early hepatocellular carcinoma: progression from early to advanced. , 1996, Seminars in surgical oncology.

[34]  M. Loda,et al.  CDC25 phosphatases as potential human oncogenes. , 1995, Science.

[35]  James M. Roberts,et al.  Inhibitors of mammalian G1 cyclin-dependent kinases. , 1995, Genes & development.

[36]  C. Sherr.  G1 phase progression: Cycling on cue , 1994, Cell.

[37]  S. Fan,et al.  Prognostic significance of proliferating cell nuclear antigen expression in hepatocellular carcinoma , 1994, Cancer.

[38]  H Nojima,et al.  Cdc25A is a novel phosphatase functioning early in the cell cycle. , 1994, The EMBO journal.

[39]  N. Nishida,et al.  Molecular aspects of hepatocarcinogenesis and their clinical implications - review. , 1994, International journal of oncology.

[40]  M. Tsuneyoshi,et al.  Proliferating cell nuclear antigen in hepatocellular carcinoma and small cell liver dysplasia , 1993, Cancer.

[41]  C. J. Chen,et al.  Amplification and overexpression of cyclin D1 in human hepatocellular carcinoma. , 1993, Biochemical and biophysical research communications.

[42]  T. Bauer,et al.  Ki‐67‐determined growth fraction versus standard staging and grading parameters in colorectal carcinoma: A multivariate analysis , 1992, Cancer.

[43]  P. Lipponen,et al.  Prognostic value of cell proliferation in breast cancer as determined by proliferating cell nuclear antigen (PCNA) immunostaining. , 1992, Anticancer research.

[44]  H. Piwnica-Worms,et al.  p107wee1 is a dual-specificity kinase that phosphorylates p34cdc2 on tyrosine 15. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[45]  D. Beach,et al.  Specific activation of cdc25 tyrosine phosphatases by B-type cyclins: Evidence for multiple roles of mitotic cyclins , 1991, Cell.

[46]  S. Hirohashi,et al.  Aberrations of the tumor suppressor p53 and retinoblastoma genes in human hepatocellular carcinomas. , 1991, Cancer research.

[47]  A Nagata,et al.  An additional homolog of the fission yeast cdc25+ gene occurs in humans and is highly expressed in some cancer cells. , 1991, The New biologist.

[48]  K. Sadhu,et al.  Human homolog of fission yeast cdc25 mitotic inducer is predominantly expressed in G2. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[49]  G. Peters,et al.  Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer. , 1996, Advances in cancer research.