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Immunohistochemical Analysis for the Expression of DR5 TRAIL Receptor and p53 in Non-small Cell Lung Cancer

Tuberculosis & Respiratory Diseases / Tuberculosis & Respiratory Diseases,
2008, v.64 no.4, pp.278-284




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Abstract

Background: TRAIL is a promising anticancer agent which induces selective tumor cell death due to a unique receptor system that includes death receptors and decoy receptors. DR5 TRAIL receptor is an originally identified p53-regulated death receptor gene that was induced, by doxorubicine, only in cells with a wild-type p53 status. We investigated that focused on the correlation between the DR5 and p53 expressions in non-small cell lung cancer(NSCLC). Methods: Immunohistochemical analysis, with using avidin-biotinylated horseradish peroxidase complex, was carried out in 89 surgically resected NSCLC formalin-fixed paraffin-embedded tissue sections. As primary antibodies, we used anti-DR5 polyclonal antibody and anti-p53 monoclonal antibody. A negative control was processed with each slide. The positive tumor cells were quantified twice and these values were expressed as percentage of the total number of tumor cells, and the intensity of immunostaining was expressed. The analysis of the DR5 expression was done separately in tumor area and in a nearby region of normal tissue. Results: The DR5 expression was high in the bronchial epithelium (89% of cases) but this was almost absent in type I & II pneumocytes, lymphocytes and smooth muscle cells. High DR5 expression rate in tumor was seen in 28% (15/53) of squamous cell carcinomas, in 47% (15/32) of adenocarcinomas and, in 50% (2/4) of large cell carcinomas. The DR5 expression did not show any statistical significance relationship with the T stage, N stage, or survival. However, the DR5 expression showed significant inverse correlation with the p53 expression. (p<0.01).Conclusion: We demonstrated that the DR5 expression in NSCLC via immunohistochemical analysis is relatively tumor-specific except for that in the normal bronchial epithelium and it is significantly dependent on the p53 status. This might be in vivo evidence for the significance of the DR5 gene as a p53 downstream gene.

keywords
TRAIL, DR5, p53, NSCLC

Reference

1.

1. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305-8.

2.

2. Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA,Marsters SA, et al. Safety and antitumor activity of recombinant soluble Apo2 ligand. J Clin Invest 1999;104:155-62.

3.

3. Lawrence D, Shahrokh Z, Marsters S, Achilles K, Shih D, Mounho B, et al. Differential hepatocyte toxicity of recombinant Apo2L/TRAIL versions. Nat Med 2001;7:383-5.

4.

4. Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS,Kubin M, et al. Tumoricidal activity of tumor necrosis factor-related apoptosis-inducing ligand in vivo. Nat Med 1999;5:157-63.

5.

5. Wu GS, Burns TF, McDonald ER 3rd, Jiang W, Meng R, Krantz ID, et al. KILLER/DR5 is a DNA damage-inducible p53-regulated death receptor gene. Nat Genet1997;17:141-3.

6.

6. Kim K, Takimoto R, Dicker DT, Chen Y, Gazitt Y,El-Deiry WS. Enhanced TRAIL sensitivity by p53 overexpression in human cancer but not normal cell lines.Int J Oncol 2001;18:241-7.

7.

7. Jang SH, Seol JY, Kim CH, Yoo CG, Kim YW, Han SK,et al. Additive effect of TRAIL and p53 gene transfer on apoptosis of human lung cancer cell lines. Int J Mol Med 2004;13:181-6.

8.

8. Bremer E, van Dam G, Kroesen BJ, Leij L, Helfrich W.Targeted induction of apoptosis cancer therapy: current progress and prospects. Trends Mol Med 2006;12:382-93.

9.

9. Gajewski TF. On the TRAIL toward death receptorbased cancer therapeutics. J Clin Oncol 2007;25:1305-7.

10.

10. Tolcher AW, Mita M, Meropol NJ, von Mehren M,Patnaik A, Padavic K, et al. Phase I pharmacokinetic and biologic correlative study of mapatumumab, a fully human monoclonal antibody with agonist activity to tumor necrosis factor-related apoptosis-inducing ligand receptor-1. J Clin Oncol 2007;25:1390-5.

11.

11. Cretney E, Uldrich AP, Berzins SP, Strasser A, Godfrey DI, Smyth MJ. Normal thymocyte negative selection in TRAIL-deficient mice. J Exp Med 2003;198:491-6.

12.

12. Lee SH, Shin MS, Kim HS, Lee HK, Park WS, Kim SY,et al. Alterations of the DR5/TRAIL receptor 2 gene in non-small cell lung cancers. Cancer Res 1999;59:5683-6.

13.

13. Wu WG, Soria JC, Wang L, Kemp BL, Mao L. TRAIL-R2 is not correlated with p53 status and is rarely mutated in non-small cell lung cancer. Anticancer Res 2000;20:4525-9.

14.

14. Spierings DC, de Vries EG, Timens W, Groen HJ,Boezen HM, de Jong S. Expression of TRAIL and TRAIL death receptors in stage III non-small cell lung cancer tumors. Clin Cancer Res 2003;9:3397-405.

15.

15. Mitsiades N, Poulaki V, Mitsiades C, Tsokos M. Ewing's sarcoma family tumors are sensitive to tumor necrosis factor-related apoptosis-inducing ligand and express death receptor 4 and death receptor 5. Cancer Res 2001;61:2704-12.

16.

16. Zhang XD, Franco A, Myers K, Gray C, Nguyen T,Hersey P. Relation of TNF-related apoptosis-inducing ligand (TRAIL) receptor and FLICE-inhibitory protein expression to TRAIL-induced apoptosis of melanoma.Cancer Res 1999;59:2747-53.

17.

17. Zhang XD, Franco AV, Nguyen T, Gray CP, Hersey P.Differential localization and regulation of death and decoy receptors for TNF-related apoptosis-inducing ligand(TRAIL) in human melanoma cells. J Immunol 2000;164:3961-70.

18.

18. El-Deiry WS. Insights into cancer therapeutic design based on p53 and TRAIL receptor signaling. Cell Death Differ 2001;8:1066-75.

19.

19. Oren M. Decision making by p53: life, death, and cancer. Cell Death Differ 2003;10:431-42.

20.

20. Sheikh MS, Fornace AJ Jr. Death and decoy receptors and p53-mediated apoptosis. Leukemia 2000;14:1509-13.

21.

21. Liu X, Yue P, Khuri FR, Sun SY. Decoy receptor 2(DcR2) is a p53 target gene and regulates chemosensitivity.Cancer Res 2005;65:9169-75.

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