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Does the Expression of Cyclin E, pRb, and p21 Correlate with Prognosis in Gastric Adenocarcinoma?

Abstract

Background Cyclin E is a protein that plays a key role in the G1 → S transition of the normal cell cycle. The product of retinoblastoma gene (pRb) is the master regulator of entry into the cell cycle and p21 protein is a cyclin-dependent kinase inhibitor that disturbs the progression through the cell cycle. The expression of these proteins, among many others, is being deregulated in tumorogenesis. The aim of this study was to investigate whether cyclin E, pRb, and p21 can be used as prognostic indicators in gastric cancer. Material and Methods Fifty-six patients with gastric adenocarcinoma, who underwent curative resection, constituted the group of our study. The immunohistochemical expression of cyclin E, pRb, and p21 proteins was examined and correlated with clinical-pathological parameters and survival. Results Positive cyclin E immunostaining was observed in 23 tumors (41.1%). It was associated with intestinal Lauren classification (P = 0.003), nodal infiltration (P = 0.0025), size of the tumor >5 cm (P = 0.032), and lymphatic (P = 0.042) and vascular invasion (P = 0.0029). Nevertheless, the survival of patients with positive cyclin E tumors was not significantly shorter than that of negative patients. Positive pRb immunostaining was found in 24 (42.9%) cases and it was associated with the absence of Helicobacter pylori (P = 0.044), whereas positive p21 immunostaining was found in 21 tumors (37.5%) and it was associated with less depth of gastric wall infiltration (P = 0.001), the absence of lymphatic (P = 0.019) and vascular infiltration (P = 0.024), and the absence of liver metastasis (P = 0.044). Cyclin E expression was associated with pRb expression (P = 0.023), but was correlated inversely with p21 expression (P = 0.009). The survival of patients with pRb-positive tumors and the survival of patients with p21-positive tumors were significantly longer than that of negative patients (P = 0.0044 and P < 0.001, respectively). Conclusion The expression of cyclin E could not predict the survival in this series of patients with gastric cancer, whereas the expression of pRb and p21 was associated with a favorable prognosis.

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References

  1. Sherr CJ. Cancer cell cycle. Science. 1996;274:1672–1677. doi:10.1126/science.274.5293.1672.

    PubMed  Article  CAS  Google Scholar 

  2. Hartwell LH, Kastan MB. Cell cycle control and cancer. Science. 1994;266:1821–1828. doi:10.1126/science.7997877.

    PubMed  Article  CAS  Google Scholar 

  3. Puduvalli VK, Kyritsis AP, Hess KR, et al. Patterns of expression of Rb and p16 in astrocytic gliomas, and correlation with survival. Int J Oncol. 2000;17(5):963–969.

    PubMed  CAS  Google Scholar 

  4. Akama Y, Yasui W, Yokozaki H, et al. Frequent amplification of the cyclin E gene in gastric carcinoma. Jpn J Cancer Res. 1995;86:617–621.

    PubMed  CAS  Google Scholar 

  5. Yasui W, Akama Y, Kuniyasu H, et al. Expression of cyclin E in human gastric adenomas and adenocarcinomas: correlation with proliferative activity and p53 status. J Exp Ther Oncol. 1996;1:88–94.

    PubMed  CAS  Google Scholar 

  6. Yasui W, Kudo Y, Semba S, Yokozaki H, Tahara E. Reduced expression of cyclin-dependent kinase inhibitor p27Kip1 is associated with advanced stage and invasiveness of gastric carcinomas. Jpn J Cancer Res. 1997;88:625–629.

    PubMed  CAS  Google Scholar 

  7. Nakamura M, Katano M, Fujimoto K, Morisaki T. A new prognostic strategy for gastric carcinoma: mRNA expression of tumour growth-related factors in endoscopic biopsy specimens. Ann Surg. 1997;226:35–42. doi:10.1097/00000658-199707000-00005.

    PubMed  Article  CAS  Google Scholar 

  8. Jiaqing L, Hokita S, Xiangming C, et al. Role of cyclin E and p53 expression in progression of early gastric cancer. Gastric Cancer. 1998;1(2):160–165. doi:10.1007/s101200050011

    Google Scholar 

  9. Sakaguchi T, Watanabe A, Sawada H, et al. Prognostic value of cyclin E and p53 expression in gastric carcinoma. Cancer. 1998;82(7):1238–1243. doi:10.1002/(SICI)1097-0142(19980401)82:7<1238::AID-CNCR5>3.0.CO;2-B

    Google Scholar 

  10. Ahn MJ, Kim BH, Jang SJ, et al. Expression of cyclin D1 and cyclin E in human gastric carcinoma and its clinicopathologic significance. J Korean Med Sci. 1998;13(5):513–518.

    PubMed  CAS  Google Scholar 

  11. Jang SJ, Park YW, Park MH, et al. Expression of cell-cycle regulators, cyclin E and p21WAF1/CIP1, potential prognostic markers for gastric cancer. Eur J Surg Oncol. 1999;25(2):157–63. doi:10.1053/ejso.1998.0619

    Google Scholar 

  12. Aoyagi K, Koufuji K, Yano S, et al. Immunohistochemical study on the expression of cyclin D1 and E in gastric cancer. Kurume Med J. 2000;47(3):199–203.

    PubMed  CAS  Google Scholar 

  13. Bani-Hani KE, Almasri NM, Khader YS, Sheyab FM, Karam HN. Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer. Clin Cancer Res. 2005;11:1447–1453. doi:10.1158/1078-0432.CCR-04-1730.

    PubMed  Article  CAS  Google Scholar 

  14. Tenderenda M. A study on the prognostic value of cyclins D1 and E expression levels in respectable gastric cancer and on some correlations between cyclins expression, histoclinical parameters and selected protein products of cell-cycle regulatory genes. J Exp Clin Cancer Res. 2005;24(3):405–414.

    PubMed  CAS  Google Scholar 

  15. Liang B, Wang S, Yang X, Ye Y, Yu Y, Cui Z. Expressions of cyclin E cyclin dependent kinase 2 and p57 (KIP2) in human gastric cancer. Chin Med J (Engl). 2003;116:20–23.

    CAS  Google Scholar 

  16. Takano Y, Kato Y, van Diest PJ, Masuda M, Mitomi H, Okayasu I. Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. Am J Pathol. 2000;156:585–594.

    PubMed  CAS  Google Scholar 

  17. Muller W, Noguchi T, Wirtz HC, Hommel G, Gabbert HE. Expression of cell-cycle regulatory proteins cyclin D1, cyclin E, and their inhibitor p21 WAF1/CIP1 in gastric cancer. J Pathol. 1999;189:186–193. doi:10.1002/(SICI)1096-9896(199910)189:2<186::AID-PATH418>3.0.CO;2-L.

    PubMed  Article  CAS  Google Scholar 

  18. Kwon OJ, Kang HS, Suh JS, Chang MS, Jang JJ, Chung JK. The loss of p27 protein has an independent prognostic significance in gastric cancer. Anticancer Res. 1999;19:4215–4220.

    PubMed  CAS  Google Scholar 

  19. Myung N, Kim MR, Chung IP, Kim H, Jang JJ. Loss of p16 and p27 is associated with progression of human gastric cancer. Cancer Lett. 2000;153:129–136. doi:10.1016/S0304-3835(00)00359-1.

    PubMed  Article  CAS  Google Scholar 

  20. Chetty R, Sitti CW. Cyclin E immunoexpression in gastric cancer does not correlate with clinicopathological parameters. Histopathology. 2003;42:66–69. doi:10.1046/j.1365-2559.2003.01519.x.

    PubMed  Article  CAS  Google Scholar 

  21. Gomyo Y, Ikeda M, Osaki M, et al. Expression of p21 (waf1/cip1/sdi1), but not p53 protein, is a factor in survival of patients with advanced gastric carcinoma. Cancer (Phila). 1997;79:2067–2072. doi:10.1002/(SICI)1097-0142(19970601)79:11<2067::AID-CNCR3>3.0.CO;2-M.

    Article  CAS  Google Scholar 

  22. Ogawa M, Maeda K, Onoda N, Chung YS, Sowa M. Loss of p21WAF1/CIP1 expression correlates with disease progression in gastric carcinoma. Br J Cancer. 1997;75(11):1617–1620.

    PubMed  CAS  Google Scholar 

  23. Xiangming C, Hokita S, Natsugoe S, et al. p21 expression is a prognostic factor in patients with p53-negative gastric cancer. Cancer Lett. 2000;148(2):181–188. doi:10.1016/S0304-3835(99)00335-3.

    Google Scholar 

  24. Baldus SE, Schneider PM, Monig SP, et al. p21/waf1/cip1 in gastric cancer: associations with histopathological subtypes, lymphonodal metastasis, prognosis and p53 status. Scand J Gastroenterol. 2001;36(9):975–980. doi:10.1080/003655201750305512.

    Google Scholar 

  25. Okuyama T, Maehara Y, Kabashima A, Takahashi I, Kakeji Y, Sugimachi K. Combined evaluation of expressions of p53 and p21 proteins as prognostic factors for patients with gastric carcinoma. Oncology. 2002;63(4):353–361. doi:10.1159/000066223.

    Google Scholar 

  26. Kaye PV, Radebold K, Isaacs S, Dent DM. Expression of p53 and p21waf1/cip1 in gastric carcinoma: lack of inter-relationship or correlation with prognosis. Eur J Surg Oncol. 2000;26(1):39–43. doi:10.1053/ejso.1999.0738.

    Google Scholar 

  27. Feakins RM, Nickols CD, Bidd H, Walton SJ. Abnormal expression of pRb, p16, and cyclin D1 in gastric adenocarcinoma and its lymph node metastases: relationship with pathological features and survival. Hum Pathol. 2003;34(12):1276–1282. doi:10.1016/j.humpath.2003.07.005.

  28. Song HS, Kim IH, Sohn SS, Kwon KY, Lee WS. Prognostic significance of immunohistochemical expression of p53 and retinoblastoma gene protein (pRB) in curatively resected gastric cancer. Korean J Intern Med. 2005;20(1):1–7.

    PubMed  CAS  Article  Google Scholar 

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Correspondence to Gregory Kouraklis.

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Kouraklis, G., Katsoulis, I.E., Theocharis, S. et al. Does the Expression of Cyclin E, pRb, and p21 Correlate with Prognosis in Gastric Adenocarcinoma?. Dig Dis Sci 54, 1015–1020 (2009). https://doi.org/10.1007/s10620-008-0464-y

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  • DOI: https://doi.org/10.1007/s10620-008-0464-y

Keywords

  • Cyclin E
  • pRb
  • p21
  • Gastric cancer