- Research
- Published:
Lung cancer incidence and survival in chromium exposed individuals with respect to expression of anti-apoptotic protein survivin and tumor suppressor P53 protein
European Journal of Medical Research volume 15, Article number: 55 (2010)
Abstract
Objective
Workers chronically exposed to hexavalent chromium have elevated risk of lung cancer. Our study investigates the incidence of lung cancer types, age at onset of the disease, and survival time among chromium exposed workers with respect to the expression of anti-apoptotic p53 and pro-apoptotic survivin proteins.
Materials and methods
67 chromium exposed workers and 104 male controls diagnosed with lung cancer were analyzed. The mean exposure time among workers was 16.7 ± 10.0(SD) years (range 1- 41 years). To investigate the possible regulation of survivin by p53 we examined the expression of both proteins using immohistochemical visualization.
Results
Chromium exposure significantly decreases the age of onset of the disease by 3.5 years (62.2 ± 9.1 in the exposed group vs. 65.7 ± 10.5 years in controls; P = 0.018). Small cell lung carcinoma (SCLC) amounted for 25.4% of all cases in chromium exposed workers and for 16.3% in non-exposed individuals. The mean survival time in the exposed group was 9.0 ± 12.7 vs. 12.1 ± 21.9 months in controls, but this difference was not significant. Survivin was predominantly expressed in both cell nucleus and cytoplasm, whereas p53 was expressed in the nucleus. There was a negative correlation between survivin and p53 expression. A decreased intensity of expression and fewer cells positive for survivin was detected in SCLC compared with other types of lung cancer. P53 was expressed in 94.1% and survivin in 79.6% of the samples analyzed.
Conclusion
The study calls attention to decreased expression of survivin, as opposed to p53, in small cell lung carcinoma.
Introduction
Lung cancer is the world's leading cause of cancer death. It is primarily due to the inhalation of carcinogens and highly accessible to prevention by diminishing exposure to lung carcinogens. Smelters are regularly exposed to higher levels of chromium (Cr) at the workplace in comparison with non-exposed individuals; respiratory tract being the major route of exposure. Based on in vitro and animal data as well as on epidemiological [1–5] and cytogenetic studies in humans [6], IARC has classified hexavalent chromium as a carcinogen of the group I.
Entering cells, chromium induces formation of reactive intermediates, resulting in enhanced oxidative stress [7]. Oxidative stress caused by intermediates formed during chromium reduction has cyto- and genotoxic effect [8, 9]. During Cr(VI) reduction, a diverse range of genetic lesions are generated including Cr-DNA binary (mono) adducts, Cr-DNA ternary adducts, DNA protein cross-links, bi-functional (DNA inter-strand cross-links) adducts, single-strand breaks, and oxidized bases. Cr(VI) exposure elicits a classical DNA damage response within cells including activation of the p53 signaling pathway and cell cycle arrest or apoptosis [10].
Apoptosis or programmed cell death is needed for maintenance of cell homeostasis and to destroy cells that represent a threat to the integrity of the organism. Apoptosis can be induced by either specific extracellular signals or internal stimuli. The molecular mechanisms involved in apoptotic enzymatic pathway have been sufficiently reviewed [11]. Protein p53 plays an important role in apoptosis induction. It acts as a transcription factor which is in humans encoded by the TP53 gene [12, 13]. P53 is activated by various stress signals as radiation (UV, gamma), carcinogens (polycyclic aromatic carbohydrates, heavy metals), oxidative stress, hypoxia, oncogene activation, telomere shortening, and others [14]. Apoptosis induction is one of the main functions of p53.
The expression and activity of p53 are precisely regulated at many levels [15]. P53 prevents tumor formation through cell cycle, blocking and eliminating damaged cells. Mutations or inactivation of p53 are the most frequent changes in human tumorous cells [16]. On the other hand, survivin is a member of IAP gene family, which has been implicated in both inhibition of apoptosis and mitosis regulation [17]. Survivin up-regulates genes in tumor tissues [18]. High survivin expression is related to poor prognosis in many cancer types [19, 20] Some investigations have shown that p53 leads to the repression of survivin expression in non-small lung cancers [21]. There are many studies that show the expression of the mentioned proteins in non-small cell lung cancer, but only few regarding small cell carcinomas (SCLC) [22–24].
The present study focuses on the investigation of the incidence of lung cancer types, age at onset of disease, and survival time among chromium exposed workers (smelters, tapers, crane operators) with respect to the expression of anti-apoptotic p53 and proapoptotic survivin proteins.
Materials and methods
Subjects and Sampling
The study was performed in accordance with the Declaration of Helsinki for Human Research and study protocol was approved by a local ethics Committee. Data were analyzed available at the Department of Pathology of Dolny KubÃn Hospital and of the Slovak National Cancer Register covering the period 1985-2005 (278 men diagnosed with lung cancer). A hundred and seventy one cases were selected for the present study with a clear histopathological lung cancer type. According to chromium exposure two groups were formed. The exposed group consisted of 67 former workers who had contact with ferrochrome alloys, and who were diagnosed with lung cancer. The mean time of exposure was 16.7 ± 10.0 years. The control group consisted of 104 men, who also were diagnosed with lung cancer, but were never exposed to Cr or any other known carcinogen.
Exposure Data
Chromium analysis in soil and air was made in the vicinity of the workplaces. Samples were examined by atomic absorption spectrometry (Varian Spectrophotometer AA30-P, Varian B.V. Scientific Instruments, Middelburg, The Netherlands). The mean all-shift concentrations of total chromium in the air of the smelting plant were 0.03-0.19 mg m-3, the values of hexavalent chromium were between 0.019-0.03 mg m-3. The mean concentrations of total chromium in the air in the environment surrounding the workplaces and in the control area (0.0113 g m-3) did not reach the recommended norm (0.01 - 0.0117 μg m-3). In the soil, in a distance of 200 m from the workplaces, the chromium content was 137 mg kg-1, which is slightly exceeding the recommended norm of 100 mg kg-1. The chromium contents in the soil at a farther distance and from the control area were below the recommended norm (60.2 mg kg-1 and 46.0 mg kg-1, respectively).
Sixty seven samples from the study patients were suitable for the evaluation for survivin and p53 expression. The remaining specimens had to be discarded due to damage. The hematoxylin and eosin stained slides from each case were independently reviewed by two pathologists to ascertain the diagnosis based on morphological and immunohistochemical parameters and were correlated with clinical data. Three sections 4 m thick, obtained from each paraffin block, were stained for p53 and survivin proteins. To achieve greater adherence of the sections to glass surface, silanized slides (DAKO, Denmark) were used, which had been heated for 2 h in an oven at 56°C. Then the sections were deparaffinized in xylene for 20 min, rehydrated in a series of descending ethanol concentrations and washed with phosphate-buffered saline (PBS). The endogenous peroxidase activity was blocked with 3% hydrogen peroxide for 30 min. Antigen unmasking was achieved by heating the sections which had been immersed in the target solution (DAKO) within hot water bath (96°C) for 45 min. Immunohistochemical staining was performed using monoclonal mouse anti-p53 antibody (DAKO, Clone DO-7, dilution 1:50) and monoclonal mouse anti-survivin antibody (DAKO, Clone12C4, dilution 1:50). After overnight incubation, the p53 and survivin antigens were visualized by means of the LSAB Visualization System (DAKO) using 3, 3'-diaminobenzidine chromogen as a substrate; according to the manufacturer's instructions. All sections were counterstained with Mayer's hematoxylin (DAKO). Negative controls were obtained by omitting the primary antibodies.
In each case, the following features were assessed: 1) the intensity of staining; 2) the relative number of positively stained cells; and 3) the subcellular localization of p53 and survivin antigens.
Statistical elaboration was performed with a Chi2 test or Fischer's exact test to compare differences in the observed parameters between survivin and p53 immunoreactivity. Spearman's coefficient was used to estimate the correlation between parameters. All statistical calculations were performed using Microsoft excel and MedCalc v.5 software for Windows.
Results
The age at onset of disease and survival time are given in Table 1. Chromium exposure significantly decreased the age at which disease began by a mean of 3.5 years (62.2 ± 9.1 years in the exposed group compared with 65.7 ± 10.5 years in the unexposed group; P = 0.018). No significant correlation between the age at which disease began and the time of exposure was found (P > 0.05). The mean survival time in the exposed group was 9.0 ± 12.7 months compared with 12.1 ± 21.9 months in the unexposed group; but this difference was not significant (P = 0.47). Survival of more than 5 years concerned only 3 (1.7%) men.
Table 2 shows the analysis of lung cancer types. Small cell lung carcinoma (SCLC) formed 25.0% of all cases in the chromium exposed workers and 16.3% in the non-exposed individuals. No correlation was found between the age at which disease began and the time of exposure.
Table 3 shows the results of p53 and survivin expression profiles. Survivin was predominantly expressed in both nucleus and cytoplasm in 58 cases (96.7%), whereas p53 was expressed in 56 (88.9%) in the nucleus only. A majority of cases - 61 (92%) showed more than 25% of positively stained cells per field of view for p53 in comparison with only 18 cases (29%) with more than 25% of positively stained cells per field of view for surviving; the difference being significant (Chi2 = 53.8, P < 0.001). There was a negative correlation (r = -0.72) between survivin and p53 expression. It seems that p53 down-regulated the survivin expression. A comparison of non-small and small cell lung cancer types for the survivin expression and its intensity showed a significant decrease in the intensity and a fewer number of cells positive for survivin in small cell lung cancer (Chi2 = 15.3, P < 0.001; Chi2 = 8.4, P < 0.05, respectively). There was no significant difference in the intensity of expression and in the number of cells positive for p53 between small cell and non-small cell lung cancer types (Chi2 = 1.8, P > 0.06; Chi2 = 0.1, P > 0.75, respectively). Neither was there an appreciable difference in the survival time between the patients with or without p53 and survivin expression.
Discussion
Lung cancer is currently the most common cause of cancer mortality in males worldwide. This is largely due to the effect of cigarette smoking and to exposure to other carcinogens. Our previous studies [8, 25, 26] and many other epidemiological studies [27–31] show that workers in ferrochromium industry have excess risk for chromosomal injury and lung cancer and that the onset of disease starts at younger age. However, the information on the influence of chromium exposure on the age of disease onset is missing in the literature. Studies on the issue point to genetic predispositions and conclude that genetic constitution can play a role [32–37] in that the appearance of lung cancer in first-degree relatives can increase the risk of the early onset of lung cancer 5-fold [38, 39].
Concerning different lung cancer types we found that small cell lung carcinoma made up 25.0% of all cases in chromium exposed workers and 16.3% in non-exposed individuals. Similar findings were published by Kavcova et al [40], who found spinocellular lung cancer was the predominant type and 25.0% of patients had small cell lung cancer. Etzel et al [41] analyzed 230 early onset lung cancer (EOLC) and 426 later-onset cases (LOLC). In their study, median survival time was 16.7 months for EOLC and 19.2 for LOLC, and the 24-month survival time was 20.6 and 29.5%, respectively. Our findings did not show an appreciable difference in the median survival time between the exposed and non-exposed groups; 9.0 ± 12.7 and 12.1 ± 21.9 months, respectively. Only did the survival time exceed 5 years in 3 patients.
p53 is a multifunctional protein that regulates cell division and activates apoptosis. On the other hand, survivin can act as an apoptosis inhibitor which is overexpressed in many malignancies, including lung carcinoma. A lot of studies have been focused on the relationship between survivin and p53 expression, but the results obtained are quite controversial. Jin et al [42] and nakano et al [43] have suggested that survivin expression is negatively regulated by p53. They conclude that survivin gene is negatively regulated by p53 in NSCLC, and that survivin expression could inhibit apoptosis and accelerate tumor proliferation to produce more aggressive carcinomas. Some of the above outlined findings are in accordance with our results. We found a negative correlation between p53 and survivin expression, which confirms a clear relationship between these two opposite-acting proteins. However, we did not find a significant difference in survival time between patients with or without p53 and survivin expression.
Contrary results have been published by Akjurek et al [24]. The aim of his immunohistochemical study was to investigate the role of survivin in the early steps of lung carcinogenesis and non-small cell carcinomas, and its relationship with the expression of p53. The authors have found no correlation between survivin and p53 expression; however, the patients in whom survivin was expressed had a significantly worse prognosis. Other studies demonstrate a prognostic importance of p53 mutations and overexpression in lung cancer tissues [44, 45].
Molecular mechanisms of tumor progression and apoptosis are still unclear. Several predictors, such as nodal involvement, tumor stage, survivin and p53 expressions have been reported. However, the relationship between p53 or survivin and the prognosis of lung cancer patients is still controversial [46–48]. Our study calls attention to the expression of survivin in relation to p53 in small cell lung carcinoma. The results of this study suggest that survivin expression in small cell lung carcinoma is decreased in comparison with other lung cancer types. Further studies are required to confirm this suggestion, which for the time being remains speculative.
Conflicts of interest
The authors declare that they have no competing interests.
References
Furst A, Haro RT: A survey of metal carcinogenesis. Prog Exp Tumor Res 1969, 12: 102–33.
Fraumeni JF Jr: Respiratory carcinogenesis: an epidemiologic appraisal. J Natl Cancer Inst 1975, 55: 1039–46.
Maltoni C: Occupational chemical carcinogenesis: new facts, priorities and perspectives. IARC Sci Publ 1976, 13: 127–49.
Davies JM, Easton DF, Bidstrup L: Mortality from respiratory cancer and other causes in United Kingdom chromate production workers. Brit J Indust Med 1991, 48: 299–313.
Wise SS, Holmes AL, Wise JP Sr: Hexavalent chromium-induced DNA damage and repair mechanisms. Rev Environ Health 2008, 23: 39–57.
International Agency for Research on Cancer: IARC. Monographs on the Evaluation of Carcinogenic risks to Humans. In Chromium Nickel and Welding. Volume 49. Geneva, Switzerland; 1990:49–256.
Leonard SS, Roberts JR, Antonini JM, Castranova V, Shi X: PbCrO 4 mediates cellular responses via reactive oxygen species. Mol Cell Biochem 2004, 255: 171–179.
Halasova E, Bukovska E, Kukura F, Cervenova T, Oravec P, Kereskeni J: Do works concerning ferrochromium alloys mean risk for the inhabitants living in their surroundings? A cytogenetic study Biologia 2001, 56: 679–683.
Reiter RJ, Korkmaz A, Paredes SD, Manchester LC, Tan DX: Melatonin reduces oxidative/nitrosative stress due to drugs, toxins, metals, and herbicides. Neuro Endocrinol Lett 2008, 29: 609–613.
Bae D, Camilli TC, Chun G, Lal M, Wright K, O'Brien TJ, Patierno SR, Ceryak S: Bypass of hexavalent chromium-induced growth arrest by a protein tyrosine phosphatase inhibitor: enhanced survival and mutagenesis. Mutat Res 2009, 15: 40–6.
Jinz Z, El-Deiry WS: Overview of cell death signaling pathways. Cancer Biol Ther 2005, 4: 139–63. 10.4161/cbt.4.2.1508
Matlashewski G, Lamb P, Pim D, Peacock J, Crawford L, Benchimol S: Isolation and characterization of a human p53 cDNA clone: Expression of the human p53 gene. Embo J 1984, 3: 3257–62.
Isobe M, Emanuel BS, Givol D, Oren M, Croce CM: Localization of gene for human p53 tumour antigen to band 17p13. Nature 1986, 320: 84–5. 10.1038/320084a0
Pluguet and Hainaut, Genotoxic and non-genotoxic pathways of p53 induction Cancer Lett 2001, 174: 1–15. 10.1016/S0304-3835(01)00698-X
Coutts AS, Thangue N: The p53 response during DNA damage: impact of transcriptional cofactors. Biochem Soc Symp 2006, 73: 181–9.
Deng Y, Wu X: Peg3/Pw1 promotes p53-mediated apoptosis by inducing Bax translocation from cytosol to mitochondria. Proc Natl Acad Sci USA 2000, 97: 12050–5. 10.1073/pnas.97.22.12050
Altieri DC: Validating survivin as a cancer therapeutic target. Nat Rev Cancer 2003, 3: 46–54. 10.1038/nrc968
Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C, Lal A, Wang CJ, Beaudry GA, Ciriello KM, Cook BP, Dufault MR, Ferguson AT, Gao Y, He TC, Hermeking H, Hiraldo SK, Hwang PM, Lopez MA, Luderer HF, Mathews B, Petroziello JM, Polyak K, Zawel L, Kinzler KW: Analysis of human transcriptomes. Nat Genet 1999, 32: 387–8.
Kawasaki H, Altieri DC, Lu CD, Toyoda M, Tenjo T, Tanigawa N: Inhibition of apoptosis by survivin predicts shorter survival rates in colorectal cancer. Cancer Res 1998, 58: 179–85.
Yamashita S, Masuda Y, Kurizaki T, Haga Y, Murayama T, Ikei S, Kamei M, Takeno S, Kawahara K: Survivin expression predicts early recurrence in early-stage breast cancer. Anticancer res 2007, 27: 2803–8.
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: Human survivin is negatively regulated by wild-type p53 and participates in p53 dependent apoptotic pathway. Oncogen 2002, 21: 2613–22. 10.1038/sj.onc.1205353
Jin HO, Yoon SI, Seo SK, Lee HC, Woo SH, Yoo DH, Lee SJ, Choe TB, An S, Kwon TJ, Kim JI, Park MJ, Hong SI, Park IC, Rhee CH: Synergistic induction of apoptosis by sulindac and arsenic trioxide in human lung cancer A549 cells via reactive oxygen species-dependent down-regulation of survivin. Biochem Pharmacol 2006, 72: 1228–36. 10.1016/j.bcp.2006.07.026
Nakano J, Huang CL, Liu D, Sumitomo S, Yokomise H: Survivin gene expression is negatively regulated by p53 tumor supressor gene in non-small cell lung cancer. Int J Oncol 2005, 27: 1215–21.
Akyürek N, Memis L, Ekinci O, Köktürk N, oztürk C: Survivin expression in pre-invasive lesions and non-small cell lung carcinoma. Virchows Arch 2006, 449: 164–70. 10.1007/s00428-006-0239-9
Halasova E, Baska T, Kukura F, Mazurova D, Bukovska E, Dobrota D, Poliacek I, Halasa M: Lung cancer in relation to occupational and environmental chromium exposure and smoking. Neoplasma 2005, 52: 287–91.
Halasova E, Matakova T, Musak L, Polakova V, Vodicka P: Chromosomal damage and polymorphisms of DNA repair genes XRCC1 and XRCC3 in workers exposed to chromium. Neuro Endocrinol Lett 2008, 29: 658–62.
Mosavi-Jarrahi A, Mohagheghi M, Kalaghchi B, Mousavi-Jarrahi Y, Noori MK: Estimating the incidence of lung cancer attributable to occupational exposure in Iran. Popul health Metr 2009, 12: 7.
Zaebst DD, Seel EA, Yiin JH, Nowlin SJ, Chen P: Summary of retrospective asbestos and welding fume exposure estimates for a nuclear naval shipyard and their correlation with radiation exposure estimates. J Occup environ HYG 2009, 6: 404–14. 10.1080/15459620902922573
Zhou X, Li Q, Arita A, Sun H, Costa M: Effects of nickel, chromate, and arsenite on histone 3 lysine methylation. Toxicol Appl Pharmacol 2009, 236: 78–84. 10.1016/j.taap.2009.01.009
Kerger BD, Butler WJ, Paustenbach DJ, Zhang J, Li S: Cancer mortality in Chinese populations surrounding an alloy plant with chromium smelting operations. J Toxicol Environ Health A 2009, 72: 329–44. 10.1080/15287390802529898
Bruske-Hohlfeld I: Environmental and occupational risk factor for lung cancer. Methods Mol Biol 2009, 472: 3–23. 10.1007/978-1-60327-492-0_1
Yang P, Schwartz AG, McAllister AE, Swanson GM, Aston CE: Lung cancer risk in families of nonsmoking probands: heterogeneity by age at diagnosis. Genet Epidemiol 1999, 17: 253–73. 10.1002/(SICI)1098-2272(199911)17:4<253::AID-GEPI2>3.0.CO;2-K
Etzel CJ, Amos CI, Spitz MR: Risk for smoking-related cancer among relatives of lung cancer patients. Cancer res 2003, 63: 8531–35.
Schwartz AG: Genetic predisposition to lung cancer. Chest 2004, 125: 86S-9S. 10.1378/chest.125.5_suppl.86S
Bailey-Wilson JE, Amos CI, Pinney SM, Petersen GM, de Andrade M, Wiest JS, Fain P, Schwartz AG, You M, Franklin W, Klein C, Gazdar A, Rothschild H, Mandal D, Coons T, Slusser J, Lee J, Gaba C, Kupert E, Perez A, Zhou X, Zeng D, Liu Q, Zhang Q, Seminara D, Minna J, Anderson MW: A major lung cancer susceptibility locus maps to chromosome 6q23–25. Am J hum Genet 2004, 75: 460–74. 10.1086/423857
Matakidou A, Eisen T, Bridle H, O'Brien M, Mutch R, Houlston RS: Case-control study of familial lung cancer risks in UK women. Int J Cancer 2005, 116: 445–50. 10.1002/ijc.21012
Xu H, Spitz MR, Amos CI, Shete S: Complex segregation analysis reveals a multigene model for lung cancer. Hum Genet 2005, 116: 121–7. 10.1007/s00439-004-1212-9
Cassidy A, Balsan J, Vesin A, Wu X, Liloglou T, Brambilla C, Timsit JF, Field JK, EUELC Consortium: Cancer diagnosis in first-degree relatives and non-small cell lung cancer risk: results from a multi-centre case-control study in Europe. Eur J Cancer 2009, 45: 3047–53. 10.1016/j.ejca.2009.05.006
Ahn YS, Kang SK: Asbestos-related occupational cancers compensated under the Industrial Accident Compensation Insurance in Korea. Ind Health 2009, 47: 113–22. 10.2486/indhealth.47.113
Kavcova E, Rozborilova E, Baska T: Lung cancer in the current clinical practice. In 10th Central European Lung Camcer Conference, International Proceedings. Edited by: Zatloukal P, Petruzelka L. Prague, Medimond; 2006:41–4.
Etzel CJ, Lu M, Merriman K, Liu M, Vaporciyan A, Spitz MR: An epidemiologic study of early onset lung cancer. Lung Cancer 2006, 52: 129–34. 10.1016/j.lungcan.2005.11.018
Jin HO, Yoon SI, Seo SK, Lee HC, Woo SH, Yoo DH, Lee SJ, Choe TB, An S, Kwon TJ, Kim JI, Park MJ, Hong SI, Park IC, Rhee CH: Synergistic induction of apoptosis by sulindac and arsenic trioxide in human lung cancer A549 cells via reactive oxygen species-dependent down-regulation of survivin. Biochem Pharmacol 2006, 72: 1228–36. 10.1016/j.bcp.2006.07.026
Nakano J, Huang CL, Liu D, Sumitomo S, Yokomise H: Survivin gene expression is negatively regulated by p53 tumor supressor gene in non-small cell lung cancer. Int J Oncol 2005, 27: 1215–21.
Ahrendt SA, Hu Y, Buta M, McDermott MP, Benoit N, Yang SC, Wu L, Sidransky D: p53 mutations and survival in stage I non-small-cell lung cancer: results of a prospective study. J Natl Cancer Inst 2003, 95: 961–70. 10.1093/jnci/95.13.961
Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ, Sculier JP: Role of p53 as a prognostic factor for survival in lung cancer: a systematic review of the literature with a meta-analysis. Eur Respir J 2001, 18: 705–19. 10.1183/09031936.01.00062201
Mitsudomi T, Hamajima N, Ogawa M, Takahashi T: Prognostic significance of p53 alterations in patients with non-small cell lung cancer: a meta-analysis. Clin Cancer Res 2000, 6: 4055–63.
Fan J, Wang L, Jiang GN, He WX, Ding JA: The role of survivin on overall survival of non-small cell lung cancer, a meta-analysis of published literatures. Lung Cancer 2008, 61: 91–6. 10.1016/j.lungcan.2007.11.011
Yamashita S, Chujo M, Miyawaki M, Tokuishi K, Anami K, Yamamoto S, Kawahar K: Combination of p53AIP1 and survivin expression is a powerful prognostic marker in non-small cell lung cancer. J Exp Clin Cancer Res 2009, 28: 22. 10.1186/1756-9966-28-22
Acknowledgements
Supported by MZ 2007/48-UK-13 and VEGA 1/0576/10 grants.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Halasova, E., Adamkov, M., Matakova, T. et al. Lung cancer incidence and survival in chromium exposed individuals with respect to expression of anti-apoptotic protein survivin and tumor suppressor P53 protein. Eur J Med Res 15 (Suppl 2), 55 (2010). https://doi.org/10.1186/2047-783X-15-S2-55
Published:
DOI: https://doi.org/10.1186/2047-783X-15-S2-55