Tumor Biology

, Volume 35, Issue 5, pp 4257–4265 | Cite as

Strong expression of cyclin B2 mRNA correlates with a poor prognosis in patients with non-small cell lung cancer

  • Shinogu Takashima
  • Hajime Saito
  • Naoko Takahashi
  • Kazuhiro Imai
  • Satoshi Kudo
  • Maiko Atari
  • Yoshitaro Saito
  • Satoru Motoyama
  • Yoshihiro Minamiya
Research Article


Cyclin family proteins act in association with cyclin-dependent kinases (CDK) at cell cycle checkpoints to regulate the eukaryotic cell cycle. CyclinB2 contributes to G2/M transition by activating CDK1 kinase, and cyclin B2 inhibition induces cell cycle arrest. CyclinB2 is overexpressed in various human tumors, though the relationship between cyclin B2 expression and the clinicopathological characteristics of lung cancer and patient prognosis is not well understood. In the present study, therefore, we investigated the relationship between cyclin B2 mRNA expression and the prognosis of patients with non-small cell lung cancer (NSCLC). We used semiquantitative real-time reverse transcription polymerase chain reaction to assess the expression of cyclin B2 mRNA in tumor samples from 79 patients with NSCLC. We then correlated the cyclin B2 mRNA levels with clinicopathological factors. We also used immunohistochemical staining to determine the localization of expressed cyclin B2. The 5-year overall survival rates among patients with adenocarcinoma of lung expressing lower levels of cyclin B2 mRNA were significantly better than the corresponding rates among patients expressing higher levels (p = 0.004). Multivariate Cox proportional hazard analyses revealed that gender ((hazard ratio (HR), 9.81; p = 0.044)), n2 (HR, 146.26; p ≤ 0.001), and cyclin B2 mRNA high (HR, 7.21; p = 0.021) were independent factors affecting the 5-year overall survival rates. However, there was no significance in the 5-year overall survival rates among the patients with squamous cell carcinoma between expressing lower and higher level of cyclin B2 mRNA. Stronger expression of cyclin B2 mRNA in tumor cells is an independent predictor of a poor prognosis in patients with adenocarcinoma of lung.


CyclinB2 Non-small cell lung cancer Biomarker RT-PCR 



The authors wish to thank Ms. Mitsuko Sato and Ms. Jun Kodama for their secretarial support.

Conflicts of interest



  1. 1.
    Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011;61:69–90.CrossRefPubMedGoogle Scholar
  2. 2.
    Kastan MB, Bartek J. Cell-cycle checkpoints and cancer. Nature. 2004;432:316–23.CrossRefPubMedGoogle Scholar
  3. 3.
    Malumbres M, Barbacid M. Cell cycle, CDKs, and cancer: a changing paradigm. Nat Rev Cancer. 2009;9:153–66.CrossRefPubMedGoogle Scholar
  4. 4.
    Cordon-Cardo C. Mutations of cell cycle regulators. Biological and clinical implications for human neoplasia. Am J Pathol. 1995;147:545–60.PubMedPubMedCentralGoogle Scholar
  5. 5.
    Evans T, Rosenthal ET, Youngblom J, Distel D, Hunt T. Cyclin: a protein specified by maternal mRNA in sea urchin eggs that is destroyed at each cleavage division. Cell. 1983;33:389–96.CrossRefPubMedGoogle Scholar
  6. 6.
    Epstein CB, Cross FR. CLB5: a novel B cyclin from budding yeast with a role in S phase. Genes Dev. 1992;6:1695–706.CrossRefPubMedGoogle Scholar
  7. 7.
    Fitch I, Dahmann C, Surana U, Amon A, Nasmyth K, Goetsch L, et al. Characterization of four B-type cyclin genes of the budding yeast Saccharomyces cerevisiae. Mol Biol Cell. 1992;3:805–18.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Sterlacci W, Fiegl M, Hilbe W, Jamnig H, Oberaigner W, Schmid T, et al. Deregulation of p27 and cyclin D1/D3 control over mitosis is associated with unfavorable prognosis in non-small cell lung cancer, as determined in 405 operated patients. J Thorac Oncol. 2010;5:1325–36.CrossRefPubMedGoogle Scholar
  9. 9.
    Sterlacci W, Tzankov A, Veits L, Zelger B, Bihl MP, Foerster A, et al. A comprehensive analysis of p16 expression, gene status, and promoter hypermethylation in surgically resected non-small cell lung carcinomas. J Thorac Oncol. 2011;6:1649–57.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang LQ, Jiang F, Xu L, Wang J, Bai JL, Yin R, et al. The role of cyclin D1 expression and patient’s survival in non-small-cell lung cancer: a systematic review with meta-analysis. Clin Lung Cancer. 2012;13:188–95.CrossRefPubMedGoogle Scholar
  11. 11.
    Petri ET, Errico A, Escobedo L, Hunt T, Basavappa R. The crystal structure of human cyclin B. Cell Cycle. 2007;6:1342–9.CrossRefPubMedGoogle Scholar
  12. 12.
    Wu T, Zhang X, Huang X, Yang Y, Hua X. Regulation of cyclin B2 expression and cell cycle G2/m transition by menin. J Biol Chem. 2010;285:18291–300.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Shubbar E, Kovács A, Hajizadeh S, Parris TZ, Nemes S, Gunnarsdóttir K, et al. Elevated cyclin B2 expression in invasive breast carcinoma is associated with unfavorable clinical outcome. BMC Cancer. 2013;13:1. doi: 10.1186/1471-2407-13-1.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Park SH, Yu GR, Kim WH, Moon WS, Kim JH, Kim DG. NF-Y-dependent cyclin B2 expression in colorectal adenocarcinoma. Clin Cancer Res. 2007;13:858–67.CrossRefPubMedGoogle Scholar
  15. 15.
    De Martino I, Visone R, Wierinckx A, Palmieri D, Ferraro A, Cappabianca P, et al. HMGA proteins up-regulate CCNB2 gene in mouse and human pituitary adenomas. Cancer Res. 2009;69:1844–50.CrossRefPubMedGoogle Scholar
  16. 16.
    Stav D, Bar I, Sandbank J. Usefulness of CDK5RAP3, CCNB2, and RAGE genes for the diagnosis of lung adenocarcinoma. Int J Biol Markers. 2007;22:108–13.CrossRefPubMedGoogle Scholar
  17. 17.
    Goldstraw P. The 7th edition of TNM in lung cancer: what now? J Thorac Oncol. 2009;4:671–3.CrossRefPubMedGoogle Scholar
  18. 18.
    Hollstein M, Sidransky D, Vogelstein B, Harris CC. p53 mutations in human cancers. Science. 1991;253:49–53.CrossRefPubMedGoogle Scholar
  19. 19.
    Murakami I, Hiyama K, Ishioka S, Yamakido M, Kasagi F, Yokosaki Y. p53 gene mutations are associated with shortened survival in patients with advanced non-small cell lung cancer: an analysis of medically managed patients. Clin Cancer Res. 2000;6:526–30.PubMedGoogle Scholar
  20. 20.
    Rosell R, Monzo M, Molina F, Martinez E, Pifarre A, Moreno I, et al. K-ras genotypes and prognosis in non-small-cell lung cancer. Ann Oncol. 1995;6:S15–20.CrossRefPubMedGoogle Scholar
  21. 21.
    Tseng JE, Kemp BL, Khuri FR, Kurie JM, Lee JS, Zhou X, et al. Loss of Fhit is frequent in stage I non-small cell lung cancer and in the lungs of chronic smokers. Cancer Res. 1999;59:4798–803.PubMedGoogle Scholar
  22. 22.
    Gazzeri S, Gouyer V, Vour’ch C, Brambilla C, Brambilla E. Mechanisms of p16INK4A inactivation in non small-cell lung cancers. Oncogene. 1998;16:497–504.CrossRefPubMedGoogle Scholar
  23. 23.
    Sterlacci W, Fiegl M, Tzankov A. Prognostic and predictive value of cell cycle deregulation in non-small-cell lung cancer. Pathobiology. 2012;79:175–94.CrossRefPubMedGoogle Scholar
  24. 24.
    Huang LN, Wang DS, Chen YQ, Li W, Hu FD, Gong BL, et al. Meta-analysis for cyclin E in lung cancer survival. Clin Chim Acta. 2012;413:663–8.CrossRefPubMedGoogle Scholar
  25. 25.
    Volm M, Koomägi R, Mattern J, Stammler G. Cyclin A is associated with an unfavorable outcome in patients with non-small-cell lung carcinomas. Br J Cancer. 1997;75:1774–8.CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Volm M, Rittgen W, Drings P. Prognostic value of ERBB-1, VEGF, cyclin A, FOS, JUN, and MYC in patients with squamous cell lung carcinomas. Br J Cancer. 1998;77:663–9.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Cooper WA, Kohonen-Corish MR, McCaughan B, Kennedy C, Sutherland RL, Lee CS. Expression and prognostic significance of cyclin B1 and cyclin A in non-small cell lung cancer. Histopathology. 2009;55:28–36.CrossRefPubMedGoogle Scholar
  28. 28.
    Zhu CQ, Shih W, Ling CH, Tsao MS. Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. J Clin Pathol. 2006;59:790–800.CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Yoshida T, Tanaka S, Mogi A, Shitara Y, Kuwano H. The clinical significance of cyclin B1 and Wee1 expression in non-small-cell lung cancer. Ann Oncol. 2004;15:252–6.CrossRefPubMedGoogle Scholar
  30. 30.
    Chapman DL, Wolgemuth DJ. Isolation of the murine cyclin B2 cDNA and characterization of the lineage and temporal specificity of expression of the B1 and B2 cyclins during oogenesis, spermatogenesis, and early embryogenesis. Development. 1993;118:229–40.PubMedGoogle Scholar
  31. 31.
    Jackman M, Firth M, Pines J. Human cyclins B1 and B2 are localized to strikingly different structures: B1 to microtubules, B2 primarily to the Golgi apparatus. EMBO J. 1995;14:1646–54.PubMedPubMedCentralGoogle Scholar
  32. 32.
    Brandeis M, Hunt T. The proteolysis of mitotic cyclins in mammalian cells persists from the end of mitosis until the onset of S phase. EMBO J. 1996;15:5280–9.PubMedPubMedCentralGoogle Scholar
  33. 33.
    Liu JH, Wei S, Burnette PK, Gamero AM, Hutton M, Djeu JY. Functional association of TGF-beta receptor II with cyclin B. Oncogene. 1999;18:269–75.CrossRefPubMedGoogle Scholar
  34. 34.
    Furuno N, den Elzen N, Pines J. Human cyclin A is required for mitosis until mid prophase. J Cell Biol. 1999;147:295–306.CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Hagting A, Jackman M, Simpson K, Pines J. Translocation of cyclin B1 to the nucleus at prophase requires a phosphorylation-dependent nuclear import signal. Curr Biol. 1999;9:680–9.CrossRefPubMedGoogle Scholar
  36. 36.
    Hagting A, Karlsson C, Clute P, Jackman M, Pines J. MPF localization is controlled by nuclear export. EMBO J. 1998;17:4127–38.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Clute P, Pines J. Temporal and spatial control of cyclin B1 destruction in metaphase. Nat Cell Biol. 1999;1:82–7.CrossRefPubMedGoogle Scholar
  38. 38.
    Brandeis M, Rosewell I, Carrington M, Crompton T, Jacobs MA, Kirk J, et al. Cyclin B2-null mice develop normally and are fertile whereas cyclin B1-null mice die in utero. Proc Natl Acad Sci USA. 1998;95:4344–9.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Soria JC, Jang SJ, Khuri FR, Hassan K, Liu D, Hong WK, et al. Overexpression of cyclin B1 in early-stage non-small cell lung cancer and its clinical implication. Cancer Res. 2000;60:4000–4.PubMedGoogle Scholar
  40. 40.
    Taniguchi Y, Choi PJ, Li GW, Chen H, Babu M, Hearn J, et al. Quantifying E. coli proteome and transcriptome with single-molecule sensitivity in single cells. Science. 2010;329:533–8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2013

Authors and Affiliations

  • Shinogu Takashima
    • 1
  • Hajime Saito
    • 1
    • 2
  • Naoko Takahashi
    • 1
  • Kazuhiro Imai
    • 1
  • Satoshi Kudo
    • 1
  • Maiko Atari
    • 1
  • Yoshitaro Saito
    • 1
  • Satoru Motoyama
    • 1
  • Yoshihiro Minamiya
    • 1
  1. 1.Department of SurgeryAkita University School of MedicineAkitaJapan
  2. 2.Department of Surgery, Division of Thoracic SurgeryAkita University School of MedicineAkitaJapan

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