AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients

Schneider,Marc A.; Christopoulos,Petros; Muley,Thomas; Warth,Arne; Klingmueller,Ursula; Thomas,Michael; Herth,Felix J.F.; Dienemann,Hendrik; Mueller,Nikola S.; Theis,Fabian; Meister,Michael

doi:10.3892/ijo.2017.3834

AURKA, DLGAP5, TPX2, KIF11 and CKAP5: Five specific mitosis-associated genes correlate with poor prognosis for non-small cell lung cancer patients

Authors:
- Marc A. Schneider
- Petros Christopoulos
- Thomas Muley
- Arne Warth
- Ursula Klingmueller
- Michael Thomas
- Felix J.F. Herth
- Hendrik Dienemann
- Nikola S. Mueller
- Fabian Theis
- Michael Meister
View Affiliations

Affiliations: Translational Research Unit, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany, Department of Thoracic Oncology, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany, Institute of Pathology, University of Heidelberg, Heidelberg, Germany, Systems Biology of Signal Transduction, German Cancer Research Center, Heidelberg, Germany, Department of Pneumology and Critical Care Medicine, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany, Department of Surgery, Thoraxklinik at University Hospital Heidelberg, Heidelberg, Germany, Cellular Dynamics and Cell Patterning, Max Planck Institute of Biochemistry, Martinsried, Germany
Published online on: January 2, 2017 https://doi.org/10.3892/ijo.2017.3834
Pages: 365-372
Copyright: © Schneider et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The growth of a tumor depends to a certain extent on an increase in mitotic events. Key steps during mitosis are the regulated assembly of the spindle apparatus and the separation of the sister chromatids. The microtubule-associated protein Aurora kinase A phosphorylates DLGAP5 in order to correctly segregate the chromatids. Its activity and recruitment to the spindle apparatus is regulated by TPX2. KIF11 and CKAP5 control the correct arrangement of the microtubules and prevent their degradation. In the present study, we investigated the role of these five molecules in non-small cell lung cancer (NSCLC). We analyzed the expression of the five genes in a large cohort of NSCLC patients (n=362) by quantitative real-time PCR. Each of the genes was highly overexpressed in the tumor tissues compared to corresponding normal lung tissue. The correlation of the expression of the individual genes depended on the histology. An increased expression of AURKA, DLGAP5, TPX2, KIF11 and CKAP5 was associated with poor overall survival (P=0.001-0.065). AURKA was a significant prognostic marker using multivariate analyses (P=0.006). Immunofluorescence studies demonstrated that the five mitosis-associated proteins co-localized with the spindle apparatus during cell division. Taken together, our data demonstrate that the expression of the mitosis-associated genes AURKA, DLGAP5, TPX2, KIF11 and CKAP5 is associated with the prognosis of NSCLC patients.

View Figures

View References

1	Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D and Bray F: Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer. 136:E359–E386. 2015. View Article : Google Scholar
2	Youlden DR, Cramb SM and Baade PD: The International Epidemiology of Lung Cancer: geographical distribution and secular trends. J Thorac Oncol. 3:819–831. 2008. View Article : Google Scholar : PubMed/NCBI
3	Ding L, Getz G, Wheeler DA, Mardis ER, McLellan MD, Cibulskis K, Sougnez C, Greulich H, Muzny DM, Morgan MB, et al: Somatic mutations affect key pathways in lung adenocarcinoma. Nature. 455:1069–1075. 2008. View Article : Google Scholar : PubMed/NCBI
4	Sofocleous CT, Garg SK, Cohen P, Petre EN, Gonen M, Erinjeri JP, Downey RJ, Travis WD and Solomon SB: Ki-67 is an independent predictive biomarker of cancer specific and local recurrence-free survival after lung tumor ablation. Ann Surg Oncol. 20(Suppl 3): S676–S683. 2013. View Article : Google Scholar
5	Warth A, Cortis J, Soltermann A, Meister M, Budczies J, Stenzinger A, Goeppert B, Thomas M, Herth FJ, Schirmacher P, et al: Tumour cell proliferation (Ki-67) in non-small cell lung cancer: A critical reappraisal of its prognostic role. Br J Cancer. 111:1222–1229. 2014. View Article : Google Scholar : PubMed/NCBI
6	Pinsky BA and Biggins S: The spindle checkpoint: Tension versus attachment. Trends Cell Biol. 15:486–493. 2005. View Article : Google Scholar : PubMed/NCBI
7	Hannak E, Kirkham M, Hyman AA and Oegema K: Aurora-A kinase is required for centrosome maturation in Caenorhabditis elegans. J Cell Biol. 155:1109–1116. 2001. View Article : Google Scholar : PubMed/NCBI
8	Satinover DL, Brautigan DL and Stukenberg PT: Aurora-A kinase and inhibitor-2 regulate the cyclin threshold for mitotic entry in Xenopus early embryonic cell cycles. Cell Cycle. 5:2268–2274. 2006. View Article : Google Scholar : PubMed/NCBI
9	Macůrek L, Lindqvist A, Lim D, Lampson MA, Klompmaker R, Freire R, Clouin C, Taylor SS, Yaffe MB and Medema RH: Polo-like kinase-1 is activated by aurora A to promote checkpoint recovery. Nature. 455:119–123. 2008. View Article : Google Scholar
10	Mori D, Yano Y, Toyo-oka K, Yoshida N, Yamada M, Muramatsu M, Zhang D, Saya H, Toyoshima YY, Kinoshita K, et al: NDEL1 phosphorylation by Aurora-A kinase is essential for centrosomal maturation, separation, and TACC3 recruitment. Mol Cell Biol. 27:352–367. 2007. View Article : Google Scholar :
11	Di Fiore B, Ciciarello M and Lavia P: Mitotic functions of the Ran GTPase network: The importance of being in the right place at the right time. Cell Cycle. 3:305–313. 2004. View Article : Google Scholar : PubMed/NCBI
12	Bayliss R, Sardon T, Vernos I and Conti E: Structural basis of Aurora-A activation by TPX2 at the mitotic spindle. Mol Cell. 12:851–862. 2003. View Article : Google Scholar : PubMed/NCBI
13	Wong J, Lerrigo R, Jang CY and Fang G: Aurora A regulates the activity of HURP by controlling the accessibility of its microtubule-binding domain. Mol Biol Cell. 19:2083–2091. 2008. View Article : Google Scholar : PubMed/NCBI
14	Santarella RA, Koffa MD, Tittmann P, Gross H and Hoenger A: HURP wraps microtubule ends with an additional tubulin sheet that has a novel conformation of tubulin. J Mol Biol. 365:1587–1595. 2007. View Article : Google Scholar
15	Yu CT, Hsu JM, Lee YC, Tsou AP, Chou CK and Huang CY: Phosphorylation and stabilization of HURP by Aurora-A: Implication of HURP as a transforming target of Aurora-A. Mol Cell Biol. 25:5789–5800. 2005. View Article : Google Scholar : PubMed/NCBI
16	Blangy A, Lane HA, d'Hérin P, Harper M, Kress M and Nigg EA: Phosphorylation by p34cdc2 regulates spindle association of human Eg5, a kinesin-related motor essential for bipolar spindle formation in vivo. Cell. 83:1159–1169. 1995. View Article : Google Scholar : PubMed/NCBI
17	Ma N, Tulu US, Ferenz NP, Fagerstrom C, Wilde A and Wadsworth P: Poleward transport of TPX2 in the mammalian mitotic spindle requires dynein, Eg5, and microtubule flux. Mol Biol Cell. 21:979–988. 2010. View Article : Google Scholar : PubMed/NCBI
18	Cassimeris L and Morabito J: TOGp, the human homolog of XMAP215/Dis1, is required for centrosome integrity, spindle pole organization, and bipolar spindle assembly. Mol Biol Cell. 15:1580–1590. 2004. View Article : Google Scholar : PubMed/NCBI
19	Barr AR and Gergely F: MCAK-independent functions of ch-Tog/XMAP215 in microtubule plus-end dynamics. Mol Cell Biol. 28:7199–7211. 2008. View Article : Google Scholar : PubMed/NCBI
20	Koffa MD, Casanova CM, Santarella R, Köcher T, Wilm M and Mattaj IW: HURP is part of a Ran-dependent complex involved in spindle formation. Curr Biol. 16:743–754. 2006. View Article : Google Scholar : PubMed/NCBI
21	Chinn DC, Holland WS and Mack PC: Anticancer activity of the Aurora A kinase inhibitor MK-5108 in non-small-cell lung cancer (NSCLC) in vitro as monotherapy and in combination with chemotherapies. J Cancer Res Clin Oncol. 140:1137–1149. 2014. View Article : Google Scholar : PubMed/NCBI
22	Goldenson B and Crispino JD: The aurora kinases in cell cycle and leukemia. Oncogene. 34:537–545. 2015. View Article : Google Scholar
23	Melichar B, Adenis A, Lockhart AC, Bennouna J, Dees EC, Kayaleh O, Obermannova R, DeMichele A, Zatloukal P, Zhang B, et al: Safety and activity of alisertib, an investigational aurora kinase A inhibitor, in patients with breast cancer, small-cell lung cancer, non-small-cell lung cancer, head and neck squamous-cell carcinoma, and gastro-oesophageal adenocarcinoma: A five-arm phase 2 study. Lancet Oncol. 16:395–405. 2015. View Article : Google Scholar : PubMed/NCBI
24	Martens-de Kemp SR1, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ and Brakenhoff RH: Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer. Clin Cancer Res. 19:1994–2003. 2013. View Article : Google Scholar : PubMed/NCBI
25	Beasley MB, Brambilla E and Travis WD: The 2004 World Health Organization classification of lung tumors. Semin Roentgenol. 40:90–97. 2005. View Article : Google Scholar : PubMed/NCBI
26	Wittekind C: 2010 TNM system: On the 7th edition of TNM classification of malignant tumors. Pathologe. 31:331–332. 2010.In German. View Article : Google Scholar : PubMed/NCBI
27	Schneider MA, Granzow M, Warth A, Schnabel PA, Thomas M, Herth FJ, Dienemann H, Muley T and Meister M: Glycodelin: A new biomarker with immunomodulatory functions in non-small cell lung cancer. Clin Cancer Res. 21:3529–3540. 2015. View Article : Google Scholar : PubMed/NCBI
28	Bustin SA, Benes V, Garson JA, Hellemans J, Huggett J, Kubista M, Mueller R, Nolan T, Pfaffl MW, Shipley GL, et al: The MIQE guidelines: Minimum information for publication of quantitative real-time PCR experiments. Clin Chem. 55:611–622. 2009. View Article : Google Scholar : PubMed/NCBI
29	McShane LM, Altman DG, Sauerbrei W, Taube SE, Gion M and Clark GM: Statistics Subcommittee of the NCI-EORTC Working Group on Cancer Diagnostics REporting recommendations for tumour MARKer prognostic studies (REMARK). Eur J Cancer. 41:1690–1696. 2005. View Article : Google Scholar : PubMed/NCBI
30	Dinse GE and Lagakos SW: Nonparametric estimation of lifetime and disease onset distributions from incomplete observations. Biometrics. 38:921–932. 1982. View Article : Google Scholar : PubMed/NCBI
31	Mann HB and Whitney DR: On a test whether one of two random variables is stochastically larger than the other. Ann Math Stat. 18:50–60. 1947. View Article : Google Scholar
32	Kruskal WH and Wallis WA: Use of ranks in one-criterion variance analysis. J Am Stat Assoc. 47:583–621. 1952. View Article : Google Scholar
33	Fieller EC, Hartley HO and Pearson ES: Tests for rank correlation coefficients I. Biometrika. 44:470–481. 1957. View Article : Google Scholar
34	Budczies J, Klauschen F, Sinn BV, Győrffy B, Schmitt WD, Darb-Esfahani S and Denkert C: Cutoff Finder: A comprehensive and straightforward Web application enabling rapid biomarker cutoff optimization. PLoS One. 7:e518622012. View Article : Google Scholar : PubMed/NCBI
35	Fu J, Bian M, Xin G, Deng Z, Luo J, Guo X, Chen H, Wang Y, Jiang Q and Zhang C: TPX2 phosphorylation maintains metaphase spindle length by regulating microtubule flux. J Cell Biol. 210:373–383. 2015. View Article : Google Scholar : PubMed/NCBI
36	Li Y, Tang H, Sun Z, Bungum AO, Edell ES, Lingle WL, Stoddard SM, Zhang M, Jen J, Yang P, et al: Network-based approach identified cell cycle genes as predictor of overall survival in lung adenocarcinoma patients. Lung Cancer. 80:91–98. 2013. View Article : Google Scholar : PubMed/NCBI
37	Chen L, Zhuo D, Chen J and Yuan H: Screening feature genes of lung carcinoma with DNA microarray analysis. Int J Clin Exp Med. 8:12161–12171. 2015.PubMed/NCBI
38	Eguchi T, Kadota K, Chaft J, Evans B, Kidd J, Tan KS, Dycoco J, Kolquist K, Davis T, Hamilton SA, et al: Cell cycle progression score is a marker for five-year lung cancer-specific mortality risk in patients with resected stage I lung adenocarcinoma. Oncotarget. 7:35241–35256. 2016.PubMed/NCBI
39	Cuzick J, Swanson GP, Fisher G, Brothman AR, Berney DM, Reid JE, Mesher D, Speights VO, Stankiewicz E, Foster CS, et al Transatlantic Prostate Group: Prognostic value of an RNA expression signature derived from cell cycle proliferation genes in patients with prostate cancer: A retrospective study. Lancet Oncol. 12:245–255. 2011. View Article : Google Scholar : PubMed/NCBI
40	Wistuba II, Behrens C, Lombardi F, Wagner S, Fujimoto J, Raso MG, Spaggiari L, Galetta D, Riley R, Hughes E, et al: Validation of a proliferation-based expression signature as prognostic marker in early stage lung adenocarcinoma. Clin Cancer Res. 19:6261–6271. 2013. View Article : Google Scholar : PubMed/NCBI