Abstract
The purpose of this study is to identify a better potential biomarker for the prognosis of patients with non-small cell lung cancer (NSCLC). The expressions of Nek2, MCM7, and Ki-67 were evaluated in 270 NSCLC tissues using immunohistochemical and immunofluorescence techniques. Associations between protein expression and clinical pathologic characters were assessed, and the impact on overall survival was analyzed. We detected high levels of Nek2, MCM7, and Ki-67 expression in 25.9, 35.2, and 24.4 % of NSCLC tissues, respectively. Overexpressions of Nek2 were detected more frequently in high T-stage and N-stage cases (P = 0.000, 0.011). The expressions of Nek2, MCM7, and Ki-67 were correlated with each other. Kaplan-Meier curves indicated that patients with overexpression of Nek2, MCM7, and Ki-67 had a poorer overall survival rate compared to those with low expression for all stages (P = 0.000). In particular, the patients with Nek2 overexpression had the most negative prognosis. Multivariate Cox regression analysis showed that Nek2, MCM7, and Ki-67 are independent prognostic indicators for NSCLC. Our data suggest that among Nek2 kinase, MCM7, and Ki-67, it is Nek2 kinase that is the more effective tumor proliferation marker of poor prognosis for NSCLC patients. Thus, Nek2 may represent a new potential target for NSCLC therapeutic intervention.
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Siegel R, Ward E, Brawley O, Jemal A. Cancer statistics, 2011: the impact of eliminating socioeconomic and racial disparities on premature cancer deaths. CA Cancer J Clin. 2011;61:212–36.
Herbst RS, Heymach JV, Lippman SM. Lung cancer. N Engl J Med. 2008;359:1367–80.
Hotta K, Matsuo K, Ueoka H, Kiura K, Tabata M, Tanimoto M. Role of adjuvant chemotherapy in patients with resected non-small-cell lung cancer: reappraisal with a meta-analysis of randomized controlled trials. J Clin Oncol. 2004;22:3860–7.
Wu W, Baxter JE, Wattam SL, et al. Alternative splicing controls nuclear translocation of the cell cycle-regulated Nek2 kinase. J Biol Chem. 2007;282:26431–40.
Rees M, Stahl M, Klump B, Willers R, Gabbert HE, Sarbia M. The prognostic significance of proliferative activity, apoptosis and expression of DNA topoisomerase II alpha in multimodally-treated esophageal squamous cell carcinoma. Anticancer Res. 2001;21:3637–42.
Pugsley JM, Schmidt RA, Vesselle HL. The KI-67index and survival in non-small-cell lung cancer: a review and relevance to positron emission tomography. Cancer J. 2002;8:222–33.
Daidone MG, Silvestrini R. Prognostic and predictive role of proliferation indices in adjuvant therapy of breast cancer. J Natl Cancer Inst Monogr. 2001;30:27–35.
Lara PC, Rey A, Santana C, Afonso JL, Diaz JM, Gonzalez GJ, et al. The role of Ki67 proliferation assessment in predicting local control in bladder cancer patients treated by radical radiation therapy. Radiother Oncol. 1998;49(2):163–7.
Shepherd NA, Richman PI, England J. Ki-67 derived proliferative activity in colorectal adenocarcinoma with prognostic correlations. J Pathol. 1988;155:213–9.
Toyokawa G, Masuda K, Daigo Y, Cho HS, Yoshimatsu M, Takawa M, et al. Minichromosome maintenance protein 7 is a potential therapeutic target in human cancer and a novel prognostic marker of non-small-cell lung cancer. Mol Cancer. 2011;10:65.
Scholzen T, Gerdes J. The Ki-67 protein: from the known and the unknown. J Cell Physiol. 2000;182:311–22.
Lei M, Tye BK. Initiating DNA synthesis: from recruiting to activating the MCM complex. J Cell Sci. 2001;114:1447–54.
Remmele W, Schicketanz KH. Immunohistochemical determination of estrogen and progesterone receptor content in human breast cancer. Computer-assisted image analysis (QIC score) vs. subjective grading (IRS). Pathol Res Pract. 1993;189:862–6.
Hayward DG, Newbatt Y, Pickard L, et al. Identification by high throughput screening of viridin analogs as biochemical and cell-based inhibitors of the cell cycle-regulated nek2 kinase. J Biomol Screen. 2010;15:918–27.
Huang LY, Lee YS, Huang JJ, et al. Characterization of the biological activity of a potent small molecule Hec1 inhibitor TAI-1. J Exp Clin Cancer Res. 2014;33:6.
Fry AM. The Nek2 protein kinase: a novel regulator of centrosome structure. Oncogene. 2002;21:6184–94.
Fletcher L, Cerniglia GJ, Nigg EA, Yend TJ, Muschel RJ. Inhibition of centrosome separation after DNA damage: a role for Nek2. Radiat Res. 2004;162:128–35.
Hayward DG, Clarke RB, Faragher AJ, Pillai MR, Hagan IM, Fry AM. The centrosomal kinase Nek2 displays elevated levels of protein expression in human breast cancer. Cancer Res. 2004;64:7370–6.
Liu X, Gao Y, Lu Y, Zhang J, Li L, Yin F. Upregulation of NEK2 is associated with drug resistance in ovarian cancer. Oncol Rep. 2014;31:745–54.
Shuling W, Weidong L, Shuhua L, Yahong W, Ziyu L, Jing Z, et al. Abnormal expression of Nek2 and β-catenin in breast carcinoma: clinicopathological correlations. Histopathology. 2011;59:631–42.
Gozuacik D, Chami M, Lagorce D, et al. Identification and functional characterization of a new member of the human Mcm protein family: hMcm8. Nucleic Acids Res. 2003;2:570–9.
Labib K, Tercero JA, Diffley JF. Uninterrupted MCM2-7 function required for DNA replication fork progression. Science. 2000;288:1643–7.
Crevel C, Ivetic A, Ohno K, et al. Nearest neighbour analysis of MCM protein complexes in Drosophila melanogaster. Nucl Acids Res. 2001;29:4834–42.
Lee JK, Hurwitz J. Possessive DNA helicase activity of the minichromosome maintenance proteins 4, 6, 7 complexes requires forked DNA structures. Proc Natl Acad Sci U S A. 2001;98:54–9.
Fujioka S, Shomori K, Nishihara K, Yagama K, Nosaka K, Araki K, et al. Expression of minichromosome maintenance 7 (MCM7) in small lung adenocarcinomas (pT1): prognostic implication. Lung Cancer. 2009;65:223–9.
Marnerides A, Vassilakopoulos TP, Boltetsou E, et al. Immunohistochemical expression and prognostic significance of CCND3, MCM2 and MCM7 in Hodgkin lymphoma. Anticancer Res. 2011;31:3585–94.
Lobato S, Tafuri A, Fernandes PA, Caliari MV, et al. Minichromosome maintenance 7 protein is a reliable biological marker for human cervical progressive disease. J Gynecol Oncol. 2012;23:11–5.
Acknowledgments
This study was supported by the National Natural Science Foundation of China (No. 30971137, 81272605). Xinwen Zhong and Xiaojiao Guan contributed equally to this work. We thank MedSci for excellent lingual revision.
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Zhong, X., Guan, X., Dong, Q. et al. Examining Nek2 as a better proliferation marker in non-small cell lung cancer prognosis. Tumor Biol. 35, 7155–7162 (2014). https://doi.org/10.1007/s13277-014-1935-8
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DOI: https://doi.org/10.1007/s13277-014-1935-8