Abstract
Survivin is a member of the inhibitors of apoptosis and frequently overexpressed in various cancer cells. Overexpression of survivin in lung cancer cells attenuates antitumor effect of tyrosine kinase inhibitors. However, data from the previous studies on the clinicopathologic implication of survivin in non-small-cell lung carcinoma (NSCLC) are inconsistent. We investigated the expression of survivin in 373 cases of surgically resected NSCLC. Correlations between the expression of survivin and clinicopathologic, molecular features and prognostic significance were analyzed. In adenocarcinoma, the increased expression of survivin was associated with the presence of vascular invasion, lymph node metastasis, and tumor recurrences, but we didn’t find any correlation with survivin expression and clinicopathological parameters in squamous cell carcinoma. Patients with high survivin expression had significantly shorter disease-free survival (DFS; 42.2 vs. 58.8 months; p = 0.001) and shorter overall survival (OS; 60.8 vs. 71.5 months; p = 0.009) than those with low survivin expression group in adenocarcinoma. In squamous cell carcinoma, the expression of survivin was not associated with prognosis of the patients (DFS; 48.9 vs. 48.7 months; p = 0.837, OS; 61.0 vs. 62.4 months; p = 0.771). Multivariate analysis confirmed that survivin was an independent poor prognostic factor in adenocarcinoma (DFS: hazard ratio (HR), 1.687; 95 % confidence interval (CI), 1.123–2.532; p = 0.012; OS: HR, 1.965; 95 % CI, 1.108–3.486; p = 0.021). There was no statistically significant difference in the expression of survivin among different molecular subgroups (p > 0.05). Our results suggest that survivin is an independent negative prognostic factor in adenocarcinoma, but not in squamous cell carcinoma. The different prognostic roles played by survivin in adenocarcinoma and squamous cell carcinoma highlights the biological differences between these two histologic types.
Similar content being viewed by others
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61(2):69–90. doi:10.3322/caac.20107
Herbst RS, Heymach JV, Lippman SM (2008) Lung cancer. N Engl J Med 359(13):1367–1380. doi:10.1056/NEJMra0802714
Goldstraw P, Ball D, Jett JR, Le Chevalier T, Lim E, Nicholson AG, Shepherd FA (2011) Non-small-cell lung cancer. Lancet 378(9804):1727–1740. doi:10.1016/S0140-6736(10)62101-0
Singhal S, Vachani A, Antin-Ozerkis D, Kaiser LR, Albelda SM (2005) Prognostic implications of cell cycle, apoptosis, and angiogenesis biomarkers in non-small cell lung cancer: a review. Clin Cancer Res 11(11):3974–3986. doi:10.1158/1078-0432.CCR-04-2661
Shivapurkar N, Reddy J, Chaudhary PM, Gazdar AF (2003) Apoptosis and lung cancer: a review. J Cell Biochem 88(5):885–898. doi:10.1002/jcb.10440
Sah NK, Khan Z, Khan GJ, Bisen PS (2006) Structural, functional and therapeutic biology of survivin. Cancer Lett 244(2):164–171. doi:10.1016/j.canlet.2006.03.007
Ambrosini G, Adida C, Altieri DC (1997) A novel anti-apoptosis gene, survivin, expressed in cancer and lymphoma. Nat Med 3(8):917–921. doi:10.1038/nm0897-917
Zhang LQ, Wang J, Jiang F, Xu L, Liu FY, Yin R (2012) Prognostic value of survivin in patients with non-small cell lung carcinoma: a systematic review with meta-analysis. PLoS One 7(3):e34100. doi:10.1371/journal.pone.0034100
Hinnis AR, Luckett JC, Walker RA (2007) Survivin is an independent predictor of short-term survival in poor prognostic breast cancer patients. Br J Cancer 96(4):639–645. doi:10.1038/sj.bjc.6603616
Nakanishi K, Kawai T, Kumaki F, Hiroi S, Mukai M, Ikeda E (2003) Survivin expression in atypical adenomatous hyperplasia of the lung. Am J Clin Pathol 120(5):712–719. doi:10.1309/GWTN-2JTA-N6K7-3YDE
Akyurek N, Memis L, Ekinci O, Kokturk N, Ozturk C (2006) Survivin expression in pre-invasive lesions and non-small cell lung carcinoma. Virchows Arch 449(2):164–170. doi:10.1007/s00428-006-0239-9
Falleni M, Pellegrini C, Marchetti A, Oprandi B, Buttitta F, Barassi F, Santambrogio L, Coggi G, Bosari S (2003) Survivin gene expression in early stage non-small cell lung cancer. J Pathol 200(5):620–626. doi:10.1002/path.1388
Leist M, Jaattela M (2001) Four deaths and a funeral: from caspases to alternative mechanisms. Nat Rev Mol Cell Biol 2(8):589–598. doi:10.1038/35085008
Fan J, Wang L, Jiang GN, He WX, Ding JA (2008) The role of survivin on overall survival of non-small cell lung cancer, a meta-analysis of published literatures. Lung Cancer 61(1):91–96. doi:10.1016/j.lungcan.2007.11.011
Shinohara ET, Hallahan DE, Lu B (2004) The use of antisense oligonucleotides in evaluating survivin as a therapeutic target for radiation sensitization in lung cancer. Biol Proced Online 6:250–256. doi:10.1251/bpo95
Coumar MS, Tsai FY, Kanwar JR, Sarvagalla S, Cheung CH (2013) Treat cancers by targeting survivin: just a dream or future reality? Cancer Treat Rev. doi:10.1016/j.ctrv.2013.02.002
Tolcher AW, Mita A, Lewis LD, Garrett CR, Till E, Daud AI, Patnaik A, Papadopoulos K, Takimoto C, Bartels P, Keating A, Antonia S (2008) Phase I and pharmacokinetic study of YM155, a small-molecule inhibitor of survivin. J Clin Oncol 26(32):5198–5203. doi:10.1200/JCO.2008.17.2064
Atikcan S, Unsal E, Demirag F, Koksal D, Yilmaz A (2006) Correlation between survivin expression and prognosis in non-small cell lung cancer. Respir Med 100(12):2220–2226. doi:10.1016/j.rmed.2006.02.031
West L, Vidwans SJ, Campbell NP, Shrager J, Simon GR, Bueno R, Dennis PA, Otterson GA, Salgia R (2012) A novel classification of lung cancer into molecular subtypes. PLoS One 7(2):e31906. doi:10.1371/journal.pone.0031906
Okamoto K, Okamoto I, Okamoto W, Tanaka K, Takezawa K, Kuwata K, Yamaguchi H, Nishio K, Nakagawa K (2010) Role of survivin in EGFR inhibitor-induced apoptosis in non-small cell lung cancers positive for EGFR mutations. Cancer Res 70(24):10402–10410. doi:10.1158/0008-5472.CAN-10-2438
Takezawa K, Okamoto I, Nishio K, Janne PA, Nakagawa K (2011) Role of ERK-BIM and STAT3-survivin signaling pathways in ALK inhibitor-induced apoptosis in EML4-ALK-positive lung cancer. Clin Cancer Res 17(8):2140–2148. doi:10.1158/1078-0432.CCR-10-2798
Zhu CQ, Shih W, Ling CH, Tsao MS (2006) Immunohistochemical markers of prognosis in non-small cell lung cancer: a review and proposal for a multiphase approach to marker evaluation. J Clin Pathol 59(8):790–800. doi:10.1136/jcp.2005.031351
Sun PL, Seol H, Lee HJ, Yoo SB, Kim H, Xu X, Jheon S, Lee CT, Lee JS, Chung JH (2012) High incidence of EGFR mutations in Korean men smokers with no intratumoral heterogeneity of lung adenocarcinomas: correlation with histologic subtypes, EGFR/TTF-1 expressions, and clinical features. J Thorac Oncol 7(2):323–330. doi:10.1097/JTO.0b013e3182381515
Kim H, Yoo SB, Choe JY, Paik JH, Xu X, Nitta H, Zhang W, Grogan TM, Lee CT, Jheon S, Chung JH (2011) Detection of ALK gene rearrangement in non-small cell lung cancer: a comparison of fluorescence in situ hybridization and chromogenic in situ hybridization with correlation of ALK protein expression. J Thorac Oncol 6(8):1359–1366. doi:10.1097/JTO.0b013e31821cfc73
Huang LN, Wang DS, Chen YQ, Zhao CL, Gong BL, Jiang AB, Jia W, Hu FD (2013) Expression of survivin and patients survival in non-small cell lung cancer: a meta-analysis of the published studies. Mol Biol Rep 40(2):917–924. doi:10.1007/s11033-012-2132-8
Vischioni B, van der Valk P, Span SW, Kruyt FA, Rodriguez JA, Giaccone G (2004) Nuclear localization of survivin is a positive prognostic factor for survival in advanced non-small-cell lung cancer. Ann Oncol 15(11):1654–1660. doi:10.1093/annonc/mdh436
Rosato A, Menin C, Boldrin D, Santa SD, Bonaldi L, Scaini MC, Del Bianco P, Zardo D, Fassan M, Cappellesso R, Fassina A (2013) Survivin expression impacts prognostically on NSCLC but not SCLC. Lung Cancer 79(2):180–186. doi:10.1016/j.lungcan.2012.11.004
McDoniels-Silvers AL, Stoner GD, Lubet RA, You M (2002) Differential expression of critical cellular genes in human lung adenocarcinomas and squamous cell carcinomas in comparison to normal lung tissues. Neoplasia 4(2):141–150. doi:10.1097/01.pai.0000201808.35931.78
Perez-Moreno P, Brambilla E, Thomas R, Soria JC (2012) Squamous cell carcinoma of the lung: molecular subtypes and therapeutic opportunities. Clin Cancer Res 18(9):2443–2451. doi:10.1158/1078-0432.CCR-11-2370
Acknowledgments
This work was supported by grant no. 02-2013-044 from the Seoul National University Bundang Hospital and partly supported by a grant from the Korea Healthcare technology R&D project, Ministry of Health & Welfare, Republic of Korea (A111405).
Disclosure
The authors declare that they have no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Sun, PL., Jin, Y., Kim, H. et al. Survivin expression is an independent poor prognostic marker in lung adenocarcinoma but not in squamous cell carcinoma. Virchows Arch 463, 427–436 (2013). https://doi.org/10.1007/s00428-013-1462-9
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-013-1462-9