Comparative Expression of Apoptotic Markers in Lung Adenocarcinoma and Squamous Cell Carcinoma

  • I. Porębska
  • M. Kosacka
  • E. Sobańska
  • E. Wyrodek
  • R. Jankowska
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 873)

Abstract

Lung cancer is still an oncology challenge. A 5-year survival reaches less than 20 % of patients. Apoptosis disturbances are a key step in cancer development. The evaluation of apoptosis markers has a great potential in lung cancer. The goal of our study was a comparative evaluation of apoptosis regulators: p53, Bcl-2, Bax, COX-2, and survivin in lung adenocarcinoma (AC) and squamous cell carcinoma (SCC). We also evaluated the relationship between apoptosis markers and clinicopathological parameters. Fifty six patients with non-small cell lung cancer (NSCLC) were included into the study (20 women and 36 men). AC was diagnosed in 30 and SCC in 26 cases. The evaluation of markers was performed using an immunohistochemical method on paraffin embedded tissue specimens. We used monoclonal antibodies for p53, bcl-2, and COX2-proteins (clone DO7, bcl-2/100/D5, and 4H12, respectively), Bax (B-9 clone) and survivin (clone 12C4). The results of immunostaining were viewed by light microscopy. We revealed significantly more frequent expression of Bax and survivin in lung AC than SCC (p < 0.01 and p < 0.019). Bcl-2 immunoreactivity was seen more often in AC without lymph node metastases than with metastases (p = 0.046). There was no correlation between the apoptosis markers and gender or the presence of vessel emboli. A greater variability in markers expression was seen in lung AC than SCC. There were significant differences in the Bax and survivin expression in the two major pathological types of NSCLC. We did not revealed any correlation between the markers and TNM characteristics, accept for Bcl-2 presence along with the lymph node involvement in the AC group.

Keywords

Bax Bcl-2 COX-2 Immunohistochemistry Lung cancer p53 Survivin 

References

  1. Achiwa H, Yatabe Y, Hida T, Kuroishi T, Kozaki T, Nakamura S, Ogawa M, Sugiura T, Mitsudomi T, Takahashi T (1999) Prognostic significance of elevated cyclooxygenase 2 expression in primary, resected lung adenocarcinomas. Clin Cancer Res 5:1001–1005PubMedGoogle Scholar
  2. Cheng-Xiong X, Hua J, Myung-Haing C (2009) Apoptosis and apoptosis-based therapy in lung cancer. Anticancer Agents Med Chem 9:952–957CrossRefGoogle Scholar
  3. Cory S, Huang DC, Adams JM (2003) The Bcl-2 family: roles in cell survival and oncogenesis. Oncogene 22:8590–8607CrossRefPubMedGoogle Scholar
  4. Daraselia N, Wang Y, Budoff A, Lituev A, Potapova O, Vansant G, Monforte J, Mazo I, Ossovskaya VS (2012) Molecular signature and pathway analysis of human primary squamous and adenocarcinoma lung cancers. Am J Cancer Res 2:93–103PubMedCentralPubMedGoogle Scholar
  5. Dohi T, Altieri DC (2005) Mitochondrial dynamics of survivin and ‘four dimensional’ control of tumor cell apoptosis. Cell Cycle 4:21–23CrossRefPubMedGoogle Scholar
  6. Duarte ML, de Moraes E, Pontes E, Schluckebier L, de Moraes JL, Hainaut P, Ferreira CG (2009) Role of p53 in the induction of cyclooxygenase-2 by cisplatin or paclitaxel in non-small cell lung cancer cell lines. Cancer Lett 279:57–64CrossRefPubMedGoogle Scholar
  7. Edelman MJ, Watson D, Wang X, Morrison C, Kratzke RA, Jewell S, Hodgson L, Mauer AM, Gajra A, Masters GA, Bedor M, Vokes EE, Green MJ (2008) Eicosanoid modulation in advanced lung cancer: cyclooxygenase-2 expression is a positive predictive factor for celecoxib + chemotherapy. Cancer and Leukemia Group B Trial 30203. J Clin Oncol 26:848–855CrossRefPubMedGoogle Scholar
  8. GLOBCAN (2012) Estimated cancer incidence, mortality and prevalence worldwide, WHO, IARC. http://globocan.iarc.fr/Pages/fact_sheets_cancer.aspx. Accessed on 10 May 2014
  9. Greenhough A, Smartt HJ, Moore AE, Roberts HR, Willimas AC, Paraskeva C, Kaidi A (2009) The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumor microenvironment. Carcinogenesis 30:377–386CrossRefPubMedGoogle Scholar
  10. Groen HJ, Sietsma H, Vincent A, Hochstenbag MM, van Putten JW, van den Berg A, Dalesio O, Biesma B, Smit HJ, Termeer A, Hiltermann TJ, van den Borne BE, Schramel FM (2011) Randomized, placebo-controlled phase III study of docetaxel plus carboplatin with celecoxib and cyclooxygenase-2 expression as a biomarker for patients with advanced non-small-cell lung cancer: the NVALT-4 study. J Clin Oncol 10:4320–4326CrossRefGoogle Scholar
  11. Han PH, Li XJ, Qin H, Yao J, DU N, Ren H (2009) Upregulation of survivin in non-small cell lung cancer and its clinicopathological correlation with p53 and Bcl-2. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi 25:710–713PubMedGoogle Scholar
  12. Harada T, Ogura S, Yamazaki K, Kinoshita I, Itoh T, Isobe H, Yamashiro K, Dosaka-Akita H, Nishimura M (2003) Predictive value of expression of P53, Bcl-2 and lung resistance-related protein for response to chemotherapy in non-small cell lung cancer. Cancer Sci 9:394–399CrossRefGoogle Scholar
  13. Hida T, Yatabe Y, Achiwa H, Muramatsu H, Kozaki K, Nakamura S, Ogawa M, Mitsudomi T, Sugiura T, Takahashi T (1998) Increased expression of cyclooxygenase 2 occurs frequently in human lung cancers, specifically in adenocarcinomas. Cancer Res 58:3761–3764PubMedGoogle Scholar
  14. Hosomi Y, Yokose T, Hirose Y, Nakajima R, Nagai K, Nishiwaki Y, Ochiai A (2000) Increased cyclooxygenase 2 (COX-2) expression occurs frequently in precursor lesions of human adenocarcinoma of the lung. Lung Cancer 30:73–81CrossRefPubMedGoogle Scholar
  15. Kim GY, Lim S-J, Kim YW (2011) Expression of HuR, COX-2, and survivin in lung cancers; cytoplasmic HuR stabilizes cyclooxygenase-2 in squamous cell carcinomas. Mod Pathol 24:1336–1347CrossRefPubMedGoogle Scholar
  16. Lai RS, Wang JS, Hsu HK, Chang HC, Lin CH, Lin MC (2002) Prognostic evaluation of the expression of p53 and bcl-2 oncoproteins in patients with surgically resected non-small cell lung cancer. Jpn J Clin Oncol 32:393–397CrossRefPubMedGoogle Scholar
  17. Milas I, Komaki R, Hachiya T, Bubb SR, Ro JY, Langford L, Sawaya R, Putnam JB, Allen P, Cox JD, McDonnell TJ, Brock W, Hong WK, Roth JA, Milas L (2003) Epidermal growth factor receptor, cyclooxygenase-2, and Bax expression in the primary non-small cell lung cancer and brain metastases. Clin Cancer Res 9:1070–1076PubMedGoogle Scholar
  18. Mirsadraee S, Oswal D, Alizadeh Y, Caulo A, Van Beek E Jr (2012) The 7th lung cancer TNM classification and staging system: review of the changes and implications. World J Radiol 4:128–134PubMedCentralCrossRefPubMedGoogle Scholar
  19. Mirza A, McGuirk M, Hockenberry TN, Wu Q, Ashar H, Black S, Wen SF, Wang L, Kirschmeier P, Bishop WR, Nielsen LL, Pickett CB, Liu S (2002) Human survivin is negatively regulated by wild-type p53 and participates in p53-dependent apoptotic pathway. Oncogene 21:2613–2622CrossRefPubMedGoogle Scholar
  20. Molina MA, Simonetti S, Quiroga V, Viteri S, Campelo RG, Sanchezm J, Benlloch S, Aldeguer E, Taron M, Rosell R (2010) Survivin and CrkL expression in erlotinib-treated non-small cell lung cancer (NSCLC) patients (p) with EGFR mutations. J Clin Oncol 28(suppl):abstr e18063Google Scholar
  21. Mori S, Ito G, Usami N, Yoshioka H, Ueda Y, Kodama Y, Takahashi M, Fong KM, Shimokata K, Sekido Y (2004) p53 apoptotic pathway molecules are frequently and simultaneously altered in non small cell lung carcinoma. Cancer 15:1673–1682CrossRefGoogle Scholar
  22. Ohmura Y, Aoe M, Andou A, Shimizu N (2000) Telomerase activity and Bcl-2 expression in non-small cell lung cancer. Clin Cancer Res 6:2980–2987PubMedGoogle Scholar
  23. Porebska I, Wyrodek E, Kosacka M, Adamiak J, Jankowska R, Harłozińska-Szmyrka A (2006) Apoptotic markers p53, Bcl-2 and Bax in primary lung cancer. In Vivo 20:599–604PubMedGoogle Scholar
  24. Shivapurkar N, Reddy J, Chaudhary PM, Gazdar AF (2003) Apoptosis and lung cancer: a review. J Cell Biochem 88:885–898CrossRefPubMedGoogle Scholar
  25. Szutowicz E, Dziadziuszko R (2010) Quantitative immunohistochemistry in lung cancer: clinical perspective. Folia Histochem Cytobiol 48:7–11CrossRefPubMedGoogle Scholar
  26. Vischioni B, van der Valk P, Span SW, Kruyt FA, Rodrigez JA, Giaccone G (2004) Nuclear localization of survivin is a positive prognostic factor for survival in advanced non-small-cell lung cancer. Ann Oncol 15:1654–1660CrossRefPubMedGoogle Scholar
  27. Wistuba I (2012) Molecular pathogenesis of non-small cell lung carcinomas. J Lung Cancer 11:12–20CrossRefGoogle Scholar
  28. Yaren A, Oztop I, Kargi A, Ulukus C, Onen A, Sanli A, Binicier O, Yilmaz U, Alakavuklar M (2006) Bax, bcl-2 and c-kit expression in non-small-cell lung cancer and their effects on prognosis. Int J Clin Pract 60:675–82CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • I. Porębska
    • 1
  • M. Kosacka
    • 1
  • E. Sobańska
    • 2
  • E. Wyrodek
    • 2
  • R. Jankowska
    • 1
  1. 1.Department of Pulmonology and Lung CancerSilesian Piasts University of MedicineWroclawPoland
  2. 2.Department of Clinical ImmunologySilesian Piasts University of MedicineWroclawPoland

Personalised recommendations