Background: Cyclin-dependent kinase inhibitor p27Kip1 is a new class of tumor suppressor in a dosage dependent manner to control cell cycle progression. Human epididymis protein 4 (HE4) is a potentially useful biomarker for ovarian carcinoma, comparable with cancer antigen 125 in identifying women with ovarian cancer, both localized and advanced. However, the prognostic significance of p27Kip1 and HE4 in ovarian cancer is unclear.
Objective: Investigate the expression of p27Kip1 and HE4 in the progression of human ovarian cancer.
Material and method: Immunohistochemical analysis was performed on formalin-fixed paraffin sections of 61 specimens. The association between HE4 and p27Kip1expression and clinicopathological features was analyzed using χ2-test. For analysis of survival data, Kaplan-Meier curves were constructed, and the log-rank test was performed.
Results: The expression of p27Kip1 negatively related with HE4 expression, but it correlated significantly with lymph nodes. On the other hand, HE4 expression correlated significantly with disease stage and lymph nodes. Kaplan-Meier analysis of the survival curves of p27Kip1 and HE4 revealed a highly significant separation between low vs. high expressers in ovarian carcinoma.
Conclusion: Expression of HE4 was up-regulated significantly in human ovarian carcinoma. Overexpression of HE4 might be responsible for oncogenesis and development of ovarian carcinoma. HE4 and p27Kip1 may be of prognostic significance in human ovarian cancer.
1. Ries LAG, Kosary CL, Hankey BF, Miller BA, Clegg L, Edwards BK. SEER Cancer Statistics Review. National Cancer Institute. 1973-1998.
2. Bast RC Jr, Feeney M, Lazarus H, Nadler LM, Colvin RB, Knapp RC. Reactivity of a monoclonal antibody with human ovarian carcinoma. J Clin Invest, 1981; 68: 1331-7.
3. Ranganathan S, Simpson KJ, Shaw DC, Nicholas KR. The whey acidic protein family: a new signature motif and threedimensional structure by comparative modelling. J Mol Graph Model. 1999; 17:106-13.
4. Schalkwijk J, Wiedow O, Hirose S. The trappin gene family: proteins defined by an N terminal transglutaminase substrate domain and a C-terminal four-disulphide core. Biochem J. 1999; 340:569-77.
5. Hellström I, Raycraft J, Hayden-Ledbetter M, Ledbetter JA, Schummer M, Drescher C, et al. The HE4 (WFDC2) Protein is a biomarker for ovarian carcinoma. Cancer Res. 2003; 63:3695-700.
6. Fero ML, Randel E, Gurley KE, Roberts JM, Kemp CJ. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature. 1998; 396:177-80.
7. Lee MH, Reynisdottir I, Massague J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995; 9:639-49.
8. Polyak K, Lee MH, Erdjument-Bromage H, Koff A, Roberts JM, Tempst P, et al. Cloning of p27Kip1, a cyclindependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell. 1994; 78:59-66.
9. Catzavelos C, Bhattacharya N, Ung YC, Wilson JA, Roncari L, Sandhu C, et al. Decreased levels of the cell-cycle inhibitor p27Kip1 protein: prognostic implications in primary breast cancer. Nat Med. 1997; 3:227-30.
10. Porter PL, Malone KE, Heagerty PJ, Alexander GM, Gatti LA, Firpo EJ, et al. Expression of cell cycle regulators p27Kip1 and cyclin E, alone and in combination, correlate with survival in young breast cancer patients. Nat Med.1997; 3:222-5.
11. Cordon-Cardo C, Koff A, Drobnjak M, Capodieci P, Osman I, Millard SS, et al. Distinct altered patterns of p27KIP1 gene expression in benign prostatic hyperplasia and prostatic carcinoma. J Natl Cancer Inst. 1998; 90:1284-91.
12. Sui L, Dong Y, Ohno M, Sugimoto K, Tai Y, Hando T, et al. Implication of malignancy and prognosis of p27kip1, cyclin E, and cdk2 expression in epithelial ovarian tumors. Gynecol Oncol. 2001; 83:56-63.
13. Mori M, Mimori K, Shiraishi T, Tanaka S, Ueo H, Sugimachi K, et al. p27 expression and gastric carcinoma. Nat Med. 1997; 3:593.
14. Xu X, Yamamoto H, Sakon M, Yasui M, Ngan, CY, Fukunaga H, et al. Overexpression of CDC25A phosphatase is associated with hypergrowth activity and poor prognosis of human hepatocellular carcinomas. Clin Cancer Res. 2003; 9:1764-72.
15. Fero ML, Randel E, Gurley KE, Roberts JM and Kemp CJ. The murine gene p27Kip1 is haploinsufficient for tumour suppression. Nature. 1998; 396: 177-80.
16. Lee MH, Reynisdottir I and Massague J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995; 9:639-49.
17. Bingle L, Singleton V, Bingle CD. The putative ovarian tumour marker gene HE4 (WFDC2), is expressed in normal tissues and undergoes complex alternative splicing to yield multiple protein isoforms. Oncogene. 2002; 21:2768-73.
19. Bali A, O’Brien PM, Edwards LS, Sutherland RL, Hacker NF, Henshall SM, et al. Cyclin D1, p53, and p21Waf1/Cip1 expression is predictive of poor clinical outcome in serous epithelial ovarian cancer. Clin Cancer Res. 2004; 10:5168-77.
20. Gopfert U, Kullmann M, Hengst L. Cell cycledependent translation of p27 involves a responsive element in its 50-UTR that overlaps with a uORF. Hum Mol Genet. 2003; 12:1767-79.
21. Pagano M, Tam SW, Theodoras AM, Beer-Romero P, Del Sal G, Chau V, Yew PR, Draetta GF, Rolfe M. Role of the ubiquitin-proteasome pathway in regulating abundance of the cyclin-dependent kinase inhibitor p27. Science. 1995; 269:682-5.
22. Malek NP, Sundberg H, McGrew S, Nakayama K, Kyriakidis TR, Roberts JM. A mouse knock-in model exposes sequential proteolytic pathways that regulate p27Kip1 in G1 and S phase. Nature. 2001; 413:323-7.
23. Hara T, Kamura T, Nakayama K, Oshikawa K, Hatakeyama S, Nakayama KI. Degradation of p27Kip1 at the G0-G1 transition mediated by a Skp2-independent ubiquitination pathway. J Biol Chem. 2001; 276: 48937-43.
24. Rodier G, Montagnoli A, Di Marcotullio L, Coulombe P, Draetta GF, Pagano M, Meloche S. p27 cytoplasmic localization is regulated by phosphorylation on Ser10 and is not a prerequisite for its proteolysis. EMBO J. 2001; 20:6672-82.
25. Hara T, Kamura T, Kotoshiba S, Takahashi H, Fujiwara K, Onoyama I, Shirakawa M, Mizushima N, Nakayama KI. Role of the UBL-UBA protein KPC2 in degradation of p27 at G1 phase of the cell cycle. Mol. Cell. Biol. 2005; 25:9292-303.
26. Besson A, Gurian-West M, Chen X, Kelly-Spratt KS, Kemp CJ, Roberts JM. A pathway in quiescent cells that controls p27Kip1 stability, subcellular localization, and tumor suppression. Genes Dev. 2006; 20:47-64.
27. Kamura T, Hara T, Matsumoto M, Ishida N, Okumura F, Hatakeyama S, et al. Cytoplasmic ubiquitin ligase KPC regulates proteolysis of p27(Kip1) at G1 phase. Nat Cell Biol. 2004; 6:1229-35.
28. Ishida N, Hara T, Kamura T, Yoshida M, Nakayama K, Nakayama KI. Phosphorylation of p27Kip1 on serine 10 is required for its binding to CRM1 and nuclear export. J Biol Chem. 2002; 277:14355-8.