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British Journal of Cancer logoLink to British Journal of Cancer
. 1999 Apr;80(1-2):256–261. doi: 10.1038/sj.bjc.6690348

Comparison of deregulated expression of cyclin D1 and cyclin E with that of cyclin-dependent kinase 4 (CDK4) and CDK2 in human oesophageal squamous cell carcinoma

M Matsumoto 1,2, M Furihata 1, T Ishikawa 2, Y Ohtsuki 1, S Ogoshi 2
PMCID: PMC2363024  PMID: 10390005

Abstract

The expressions of cyclin D1, cyclin E, cyclin-dependent kinase 4 (CDK4), and CDK2 were immunohistochemically examined in 90 patients with human oesophageal squamous cell carcinoma (SCC) to determine their relationship to the tumour behaviour and patient prognosis. Nuclear immunostaining of cyclin D1 and cyclin E was observed in 28 (31.1%) and 27 tumours (30.0%) respectively. Thirty-nine tumours (43.3%) and 31 tumours (34.4%) exhibited both cytoplasmic and nuclear positivity for CDK4 and CDK2 respectively. Of 28 cyclin D1-positive and 27 cyclin E-positive tumours, CDK4 was overexpressed in 12 (42.8%) tumours and CDK2 in seven (25.9%) tumours respectively. There was no significant relationship in immunopositivity between cyclin D1 and CDK4 or between cyclin E and CDK2. Simultaneous immunoreactivity for both cyclin D1 and CDK4 was significantly associated with venous invasion (P < 0.05). In a univariate analysis, the prognosis of patients with tumours that were both cyclin D1- and CDK4-positive was significantly poorer than that of patients with cyclin D1-negative tumours (P < 0.05). In a multivariate analysis, both cyclin D1 and CDK4 immunoreactivities (P < 0.01) and tumour stage (P < 0.001) were recognized as independent risk factors. In this analysis, the hazard ratio for cyclin D1-positive and CDK4-negative cases compared with cyclin D1-negative cases was significant (hazard ratio = 3.128, 95% confidence interval = 1.418–6.899, P = 0.0047). No significant prognostic relevance was detected in both cyclin E and CDK2 immunoreactivity. Our in vivo findings suggest that in human oesophageal SCC, cyclin D1 and cyclin E and their functional partners, CDK4 and CDK2, often exhibit dysregulated overexpression in many cases, and that tumours with simultaneous expression of cyclin D1 and CDK4 are frequently associated with venous invasion and have a worse prognosis, statistically. Moreover, overexpression of cyclin D1 alone may also contribute to tumour progression independent of CDK4 overexpression. © 1999 Cancer Research Campaign

Keywords: cyclin, cyclin-dependent kinase, oesophageal squamous cell carcinoma

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Selected References

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  1. Asano K., Sakamoto H., Sasaki H., Ochiya T., Yoshida T., Ohishi Y., Machida T., Kakizoe T., Sugimura T., Terada M. Tumorigenicity and gene amplification potentials of cyclin D1-overexpressing NIH3T3 cells. Biochem Biophys Res Commun. 1995 Dec 26;217(3):1169–1176. doi: 10.1006/bbrc.1995.2892. [DOI] [PubMed] [Google Scholar]
  2. Bartkova J., Lukas J., Guldberg P., Alsner J., Kirkin A. F., Zeuthen J., Bartek J. The p16-cyclin D/Cdk4-pRb pathway as a functional unit frequently altered in melanoma pathogenesis. Cancer Res. 1996 Dec 1;56(23):5475–5483. [PubMed] [Google Scholar]
  3. Dirks P. B., Hubbard S. L., Murakami M., Rutka J. T. Cyclin and cyclin-dependent kinase expression in human astrocytoma cell lines. J Neuropathol Exp Neurol. 1997 Mar;56(3):291–300. doi: 10.1097/00005072-199703000-00008. [DOI] [PubMed] [Google Scholar]
  4. Doki Y., Imoto M., Han E. K., Sgambato A., Weinstein I. B. Increased expression of the P27KIP1 protein in human esophageal cancer cell lines that over-express cyclin D1. Carcinogenesis. 1997 Jun;18(6):1139–1148. doi: 10.1093/carcin/18.6.1139. [DOI] [PubMed] [Google Scholar]
  5. Furihata M., Ishikawa T., Inoue A., Yoshikawa C., Sonobe H., Ohtsuki Y., Araki K., Ogoshi S. Determination of the prognostic significance of unscheduled cyclin A overexpression in patients with esophageal squamous cell carcinoma. Clin Cancer Res. 1996 Oct;2(10):1781–1785. [PubMed] [Google Scholar]
  6. Furihata M., Ohtsuki Y., Ogoshi S., Takahashi A., Tamiya T., Ogata T. Prognostic significance of human papillomavirus genomes (type-16, -18) and aberrant expression of p53 protein in human esophageal cancer. Int J Cancer. 1993 May 8;54(2):226–230. doi: 10.1002/ijc.2910540211. [DOI] [PubMed] [Google Scholar]
  7. Igaki H., Sasaki H., Kishi T., Sakamoto H., Tachimori Y., Kato H., Watanabe H., Sugimura T., Terada M. Highly frequent homozygous deletion of the p16 gene in esophageal cancer cell lines. Biochem Biophys Res Commun. 1994 Sep 15;203(2):1090–1095. doi: 10.1006/bbrc.1994.2294. [DOI] [PubMed] [Google Scholar]
  8. Ishikawa T., Furihata M., Ohtsuki Y., Murakami H., Inoue A., Ogoshi S. Cyclin D1 overexpression related to retinoblastoma protein expression as a prognostic marker in human oesophageal squamous cell carcinoma. Br J Cancer. 1998;77(1):92–97. doi: 10.1038/bjc.1998.14. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Jiang W., Zhang Y. J., Kahn S. M., Hollstein M. C., Santella R. M., Lu S. H., Harris C. C., Montesano R., Weinstein I. B. Altered expression of the cyclin D1 and retinoblastoma genes in human esophageal cancer. Proc Natl Acad Sci U S A. 1993 Oct 1;90(19):9026–9030. doi: 10.1073/pnas.90.19.9026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Khatib Z. A., Matsushime H., Valentine M., Shapiro D. N., Sherr C. J., Look A. T. Coamplification of the CDK4 gene with MDM2 and GLI in human sarcomas. Cancer Res. 1993 Nov 15;53(22):5535–5541. [PubMed] [Google Scholar]
  11. Lee M. H., Reynisdóttir I., Massagué J. Cloning of p57KIP2, a cyclin-dependent kinase inhibitor with unique domain structure and tissue distribution. Genes Dev. 1995 Mar 15;9(6):639–649. doi: 10.1101/gad.9.6.639. [DOI] [PubMed] [Google Scholar]
  12. Marone M., Scambia G., Giannitelli C., Ferrandina G., Masciullo V., Bellacosa A., Benedetti-Panici P., Mancuso S. Analysis of cyclin E and CDK2 in ovarian cancer: gene amplification and RNA overexpression. Int J Cancer. 1998 Jan 5;75(1):34–39. doi: 10.1002/(sici)1097-0215(19980105)75:1<34::aid-ijc6>3.0.co;2-2. [DOI] [PubMed] [Google Scholar]
  13. Masciullo V., Scambia G., Marone M., Giannitelli C., Ferrandina G., Bellacosa A., Benedetti Panici P., Mancuso S. Altered expression of cyclin D1 and CDK4 genes in ovarian carcinomas. Int J Cancer. 1997 Aug 22;74(4):390–395. doi: 10.1002/(sici)1097-0215(19970822)74:4<390::aid-ijc5>3.0.co;2-q. [DOI] [PubMed] [Google Scholar]
  14. Motokura T., Arnold A. Cyclin D and oncogenesis. Curr Opin Genet Dev. 1993 Feb;3(1):5–10. doi: 10.1016/s0959-437x(05)80334-x. [DOI] [PubMed] [Google Scholar]
  15. Naitoh H., Shibata J., Kawaguchi A., Kodama M., Hattori T. Overexpression and localization of cyclin D1 mRNA and antigen in esophageal cancer. Am J Pathol. 1995 May;146(5):1161–1169. [PMC free article] [PubMed] [Google Scholar]
  16. Nakamura T., Sanokawa R., Sasaki Y. F., Ayusawa D., Oishi M., Mori N. Cyclin I: a new cyclin encoded by a gene isolated from human brain. Exp Cell Res. 1995 Dec;221(2):534–542. doi: 10.1006/excr.1995.1406. [DOI] [PubMed] [Google Scholar]
  17. Neuman E., Ladha M. H., Lin N., Upton T. M., Miller S. J., DiRenzo J., Pestell R. G., Hinds P. W., Dowdy S. F., Brown M. Cyclin D1 stimulation of estrogen receptor transcriptional activity independent of cdk4. Mol Cell Biol. 1997 Sep;17(9):5338–5347. doi: 10.1128/mcb.17.9.5338. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Sherr C. J. Cancer cell cycles. Science. 1996 Dec 6;274(5293):1672–1677. doi: 10.1126/science.274.5293.1672. [DOI] [PubMed] [Google Scholar]
  19. Sherr C. J. G1 phase progression: cycling on cue. Cell. 1994 Nov 18;79(4):551–555. doi: 10.1016/0092-8674(94)90540-1. [DOI] [PubMed] [Google Scholar]
  20. Sherr C. J. Mammalian G1 cyclins. Cell. 1993 Jun 18;73(6):1059–1065. doi: 10.1016/0092-8674(93)90636-5. [DOI] [PubMed] [Google Scholar]
  21. Sheyn I., Noffsinger A. E., Heffelfinger S., Davis B., Miller M. A., Fenoglio-Preiser C. M. Amplification and expression of the cyclin D1 gene in anal and esophageal squamous cell carcinomas. Hum Pathol. 1997 Mar;28(3):270–276. doi: 10.1016/s0046-8177(97)90123-4. [DOI] [PubMed] [Google Scholar]
  22. Tominaga O., Nita M. E., Nagawa H., Fujii S., Tsuruo T., Muto T. Expressions of cell cycle regulators in human colorectal cancer cell lines. Jpn J Cancer Res. 1997 Sep;88(9):855–860. doi: 10.1111/j.1349-7006.1997.tb00461.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Tsuruta H., Sakamoto H., Onda M., Terada M. Amplification and overexpression of EXP1 and EXP2/Cyclin D1 genes in human esophageal carcinomas. Biochem Biophys Res Commun. 1993 Nov 15;196(3):1529–1536. doi: 10.1006/bbrc.1993.2425. [DOI] [PubMed] [Google Scholar]
  24. Wang L. D., Shi S. T., Zhou Q., Goldstein S., Hong J. Y., Shao P., Qiu S. L., Yang C. S. Changes in p53 and cyclin D1 protein levels and cell proliferation in different stages of human esophageal and gastric-cardia carcinogenesis. Int J Cancer. 1994 Nov 15;59(4):514–519. doi: 10.1002/ijc.2910590414. [DOI] [PubMed] [Google Scholar]
  25. Weinberg R. A. The retinoblastoma protein and cell cycle control. Cell. 1995 May 5;81(3):323–330. doi: 10.1016/0092-8674(95)90385-2. [DOI] [PubMed] [Google Scholar]
  26. Zhang T., Nanney L. B., Luongo C., Lamps L., Heppner K. J., DuBois R. N., Beauchamp R. D. Concurrent overexpression of cyclin D1 and cyclin-dependent kinase 4 (Cdk4) in intestinal adenomas from multiple intestinal neoplasia (Min) mice and human familial adenomatous polyposis patients. Cancer Res. 1997 Jan 1;57(1):169–175. [PubMed] [Google Scholar]
  27. Zhou P., Jiang W., Weghorst C. M., Weinstein I. B. Overexpression of cyclin D1 enhances gene amplification. Cancer Res. 1996 Jan 1;56(1):36–39. [PubMed] [Google Scholar]
  28. Zwijsen R. M., Wientjens E., Klompmaker R., van der Sman J., Bernards R., Michalides R. J. CDK-independent activation of estrogen receptor by cyclin D1. Cell. 1997 Feb 7;88(3):405–415. doi: 10.1016/s0092-8674(00)81879-6. [DOI] [PubMed] [Google Scholar]

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