Complex analysis of the p53 tumor suppressor in lung carcinoma

Smardova,Jana; Liskova,Kvetoslava; Ravcukova,Barbora; Malcikova,Jitka; Hausnerova,Jitka; Svitakova,Miluse; Hrabalkova,Renata; Zlamalikova,Lenka; Stano-Kozubik,Katerina; Blahakova,Ivona; Speldova,Jana; Jarkovsky,Jiri; Smarda,Jan

doi:10.3892/or.2015.4533

Complex analysis of the p53 tumor suppressor in lung carcinoma

Authors:
- Jana Smardova
- Kvetoslava Liskova
- Barbora Ravcukova
- Jitka Malcikova
- Jitka Hausnerova
- Miluse Svitakova
- Renata Hrabalkova
- Lenka Zlamalikova
- Katerina Stano-Kozubik
- Ivona Blahakova
- Jana Speldova
- Jiri Jarkovsky
- Jan Smarda
View Affiliations

Affiliations: Department of Pathology, University Hospital, Brno, Czech Republic, Molecular Genetics Laboratory, Centre for Cardiovascular Surgery and Transplantation, Brno, Czech Republic, Central European Institute of Technology (CEITEC), Masaryk University, Brno, Czech Republic, Department of Respiratory Diseases and TB, University Hospital, Brno, Czech Republic, Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic, Department of Experimental Biology, Faculty of Science, Masaryk University, Brno, Czech Republic
Published online on: December 29, 2015 https://doi.org/10.3892/or.2015.4533
Pages: 1859-1867

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

Lung cancer is the leading cause of cancer-related deaths worldwide. The p53 tumor suppressor is a transcription factor controlling expression of its target genes in response to various stress stimuli. Mutations of the TP53 gene occur very frequently in lung carcinomas and they play an important role in both oncogenic transformation of lung epithelial cells and lung carcinoma progression. We determined the TP53 status in 42 samples of squamous cell lung carcinoma (SQCC) and 56 samples of lung adenocarcinoma (AC) by the functional analysis FASAY and its variant called split assay. Altogether, we detected 64 TP53 mutations in 63 patients and analyzed them by cDNA and gDNA sequencing. The TP53 mutations were found in 76.2% (32/42) of SQCC cases, and 55.4% (31/56) of ACs. Immunoblotting revealed the p53 protein accumulation in 18 samples (42.9%) among SQCC cases and 19 samples (33.9%) among AC cases. Using fluorescence in situ hybridization we detected loss of the TP53-specific 17p13.3 locus in 23 from 41 analyzed SQCC samples (56.1%) and in 20 from 54 analyzed AC samples (37.0%). We did not find any statistically significant differences in overall and disease-free survival in relation to TP53 status.

View Figures

View References

1	Siegel R, Naishadham D and Jemal A: Cancer statistics, 2013. CA Cancer J Clin. 63:11–30. 2013. View Article : Google Scholar : PubMed/NCBI
2	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
3	Harris SL and Levine AJ: The p53 pathway: Positive and negative feedback loops. Oncogene. 24:2899–2908. 2005. View Article : Google Scholar : PubMed/NCBI
4	Sherr CJ: Principles of tumor suppression. Cell. 116:235–246. 2004. View Article : Google Scholar : PubMed/NCBI
5	Haupt Y, Maya R, Kazaz A and Oren M: Mdm2 promotes the rapid degradation of p53. Nature. 387:296–299. 1997. View Article : Google Scholar : PubMed/NCBI
6	Honda R, Tanaka H and Yasuda H: Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53. FEBS Lett. 420:25–27. 1997. View Article : Google Scholar
7	Wu X, Bayle JH, Olson D and Levine AJ: The p53-mdm-2 auto-regulatory feedback loop. Genes Dev. 7:1126–1132. 1993. View Article : Google Scholar : PubMed/NCBI
8	Lin MW, Wu CT, Shih JY, Chang YL and Yang PC: Clinico-pathologic characteristics and prognostic significance of EGFR and p53 mutations in surgically resected lung adenocarcinomas ≤2 cm in maximal dimension. J Surg Oncol. 110:99–106. 2014. View Article : Google Scholar : PubMed/NCBI
9	Campling BG and El-Deiry WS: Clinical implication of p53 mutation in lung cancer. Mol Biotechnol. 24:141–156. 2003. View Article : Google Scholar : PubMed/NCBI
10	Huang CL, Yokomise H and Miyatake A: Clinical significance of the p53 pathway and associated gene therapy in non-small cell lung cancers. Future Oncol. 3:83–93. 2007. View Article : Google Scholar : PubMed/NCBI
11	Mogi A and Kuwano H: TP53 mutations in nonsmall cell lung cancer. J Biomed Biotechnol. 2011:5839292011. View Article : Google Scholar : PubMed/NCBI
12	Kishimoto Y, Murakami Y, Shiraishi M, Hayashi K and Sekiya T: Aberrations of the p53 tumor suppressor gene in human non-small cell carcinomas of the lung. Cancer Res. 52:4799–4804. 1992.PubMed/NCBI
13	Tammemagi MC, McLaughlin JR and Bull SB: Meta-analyses of p53 tumor suppressor gene alterations and clinicopathological features in resected lung cancers. Cancer Epidemiol Biomarkers Prev. 8:625–634. 1999.PubMed/NCBI
14	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
15	Cancer Genome Atlas Research Network: Comprehensive genomic characterization of squamous cell lung cancers. Nature. 489:519–525. 2012. View Article : Google Scholar : PubMed/NCBI
16	Flaman JM, Frebourg T, Moreau V, Charbonnier F, Martin C, Chappuis P, Sappino AP, Limacher IM, Bron L and Benhattar J: A simple p53 functional assay for screening cell lines, blood, and tumors. Proc Natl Acad Sci USA. 92:3963–3967. 1995. View Article : Google Scholar : PubMed/NCBI
17	Smardová J, Nemajerová A, Trbusek M, Vagunda V and Kovarík J: Rare somatic p53 mutation identified in breast cancer: A case report. Tumour Biol. 22:59–66. 2001. View Article : Google Scholar
18	Ishioka C, Frebourg T, Yan YX, Vidal M, Friend SH, Schmidt S and Iggo R: Screening patients for heterozygous p53 mutations using a functional assay in yeast. Nat Genet. 5:124–129. 1993. View Article : Google Scholar : PubMed/NCBI
19	Waridel F, Estreicher A, Bron L, Flaman JM, Fontolliet C, Monnier P, Frebourg T and Iggo R: Field cancerisation and polyclonal p53 mutation in the upper aero-digestive tract. Oncogene. 14:163–169. 1997. View Article : Google Scholar : PubMed/NCBI
20	Petitjean A, Mathe E, Kato S, Ishioka C, Tavtigian SV, Hainaut P and Olivier M: Impact of mutant p53 functional properties on TP53 mutation patterns and tumor phenotype: Lessons from recent developments in the IARC TP53 database. Hum Mutat. 28:622–629. 2007. View Article : Google Scholar : PubMed/NCBI
21	Smardová J, Smarda J and Koptíková J: Functional analysis of p53 tumor suppressor in yeast. Differentiation. 73:261–277. 2005. View Article : Google Scholar : PubMed/NCBI
22	Toyooka S, Tsuda T and Gazdar AF: The TP53 gene, tobacco exposure, and lung cancer. Hum Mutat. 21:229–239. 2003. View Article : Google Scholar : PubMed/NCBI
23	Rodin SN and Rodin AS: Origins and selection of p53 mutations in lung carcinogenesis. Semin Cancer Biol. 15:103–112. 2005. View Article : Google Scholar : PubMed/NCBI
24	Gibbons DL, Byers LA and Kurie JM: Smoking, p53 mutation, and lung cancer. Mol Cancer Res. 12:3–13. 2014. View Article : Google Scholar : PubMed/NCBI
25	Xu Y, Wang L, Zheng X, Liu G, Wang Y, Lai X and Li J: Positive expression of p53, c-erbB2 and MRP proteins is correlated with survival rates of NSCLC patients. Mol Clin Oncol. 1:487–492. 2013.
26	Steels E, Paesmans M, Berghmans T, Branle F, Lemaitre F, Mascaux C, Meert AP, Vallot F, Lafitte JJ and 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. 18:705–719. 2001. View Article : Google Scholar : PubMed/NCBI
27	Nikliński J, Niklińska W, Laudanski J, Chyczewska E and Chyczewski L: Prognostic molecular markers in non-small cell lung cancer. Lung Cancer. 34(Suppl 2): S53–S58. 2001. View Article : Google Scholar