Tuberc Respir Dis.  2007 Jul;63(1):31-41. 10.4046/trd.2007.63.1.31.

Prognostication by Cluster Analysis of COX-2, MMP-9 and P53 Expression and?by Clinico-pathologic Correlation Analysis in Non-small Cell Lung Cancer

• Shin JW
• Choi JH
• Park IW
• Yoo JH

• KMID: 1877315
• DOI: http://doi.org/10.4046/trd.2007.63.1.31

Abstract

BACKGROUND: In pathogenesis and prognosis of lung cancer, significance of enormous types of genetic expression were very compounding and undetermined. We performed this study to search association between clinical characteristics and expression of COX-2, MMP-9 and p53 in non-small cell lung cancer.
METHODS
Ninety-one patients with adenocarcinoma or squamous cell carcinoma were enrolled. We had searched clinical data retrospectively and performed immunohistochemical staining for COX-2, MMP-9 and p53. We had analyzed significance of these three genes in clinical features and prognosis for survival.
RESULTS
1) In squamous cell carcinoma, male was predominant and was significantly correlated with smoking. 2) Major prognostic determinants for overall survival were curative resection. 3) Expression of COX-2 was more frequent in adenocarcinoma than in squamous cell carcinoma. 4) Negative staining of COX-2, MMP-9 and p53 was more frequent in squamous cell carcinoma than adenocarcinoma. 5) Survival duration was longer in the group with positive expression of p53 and negative for COX-2 and MMP-9 (median duration of survival = 165.6 weeks) than groups with the other expressional patterns. 6) Significant correlation was found between expression of MMP-9 and COX-2. In squamous cell carcinoma, expression of MMP-9, COX-2 and mutant p53 were mutually correlated. 7) COX-2 expression was significant prognostic factor for survival in resected cancer group. In unresected inoperable non-small cell lung cancer group, MMP-9 was statistically significant prognostic factor for overall survival.
CONCLUSION
COX-2 and MMP-9 might have some roles for progression or prognosis in some selected patients with non-small cell lung cancer. COX-2 and MMP-9 may have some roles for disease progression or prognosis in selected patients with NSCLC.

Keyword

COX-2; MMP-9; P53; Non-small cell lung cancer

MeSH Terms

Adenocarcinoma
Carcinoma, Non-Small-Cell Lung*
Carcinoma, Squamous Cell
Cluster Analysis*
Disease Progression
Humans
Lung Neoplasms
Male
Negative Staining
Prognosis
Retrospective Studies
Smoke
Smoking
Smoke

Figure

• 

  Figure 1 Overexpression of COX-2 (A, D), MMP-9 (B, E) and p53 (C, F) in Adenocarcinoma (A, B, C) and Squamous cell carcinoma (D, E, F) of the lungs with immunohistochemical staining (×100).

• 

  Figure 2 A. Survival analysis of all study patients according to curative resection. Median survival duratrion in resected cases was 170.3 weeks (95% CI ; 109.1 - 231.5 weeks), which was more prolonged from that in inoperable cases [57.7 weeks (95% CI ; 39.6 - 75.8 weeks)](p=0.0000;Log rank test) B. Survival analysis of all study patients according to metastasis. Median survival duration in 71 cases without metastasis was 93.3 weeks (95% CI; 55.1 - 131.5 weeks) was superior to that in 20 cases with metastasis [45.4 weeks (95% CI; 15.9 - 74.9 weeks)] (p=0.0009; Log rank test). C. According to stage, median survival duration of 34 cases with early stage (stage I,II) was 170.3 weeks (95% CI; 107.2 -233.4 weeks), which was significantly longer than survival duration of 57 cases with advanced lung cancers [62.7 weeks (95% CI; 45.0 - 80.5 weeks)] (p=0.0028; Log rank test). D. Survival curves according to the expression of COX-2, MMP-9 and p53. According to COX-2 expression, positive group seemed to have shorter survival duration (88.0 weeks) than that of negative group (57.7 weeks)(p=0.08). There were no significant differences between positive and negative expression between positive versus negative group based on the expression of MMP-9 and p53.

Reference

1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005. 55:74–108.

2. Lengauer C, Kinzler KW, Vogelstein B. Genetic instabilities in human cancers. Nature. 1998. 396:643–649.

3. Lee JS, Kim SY, Hong WK, Lippman SM, Ro JY, Gay ML, et al. Detection of chromosomal polysomy in oral leukoplakia, a premalignant lesion. J Natl Cancer Inst. 1993. 85:1951–1954.

4. Ried T, Heselmeyer-Haddad K, Blegen H, Schrock E, Auer G. Genomic changes defining the genesis, progression, and malignancy potential in solid human tumors: a phenotype/genotype correlation. Genes Chromosomes Cancer. 1999. 25:195–204.

5. Phillips JL, Hayward SW, Wang Y, Vasselli J, Pavlovich C, Padilla-Nash H, et al. The consequences of chromosomal aneuploidy on gene expression profiles in a cell line model for prostate carcinogenesis. Cancer Res. 2001. 61:8143–8149.

6. Hittelman WN. Genetic instability in epithelial tissues at risk for cancer. Ann N Y Acad Sci. 2001. 952:1–12.

7. Mao L, Lee DJ, Tockman MS, Erozan YS, Askin F, Sidransky D. Microsatellite alterations as clonal markers for the detection of human cacner. Proc Natl Acad Sci U S A. 1994. 91:9871–9875.

8. Pifarre A, Rosell R, Monzo M, De Anta JM, Moreno I, Sanchez JJ, et al. Prognostic value of replication errors on chromosomes 2p and 3p in non-small cell lung cancer. Br J Cancer. 1997. 75:184–189.

9. Field JK, Neville EM, Stewart MP, Swift A, Liloglou T, Risk JM, et al. Fractional allele loss data indicate distinct genetic populations in the development of non-small cell lung cancer. Br J Cancer. 1996. 74:1968–1974.

10. Rosell R, Pifarre A, Monzo M, Astudillo J, Lopez-Cabrerizo MP, Calvo R, et al. Reduced survival in patients with stage-I non-small-cell lung cancer associated with DNA-replication errors. Int J Cancer. 1997. 74:330–334.

11. Wistuba II, Behrens C, Milchgrub S, Bryant D, Hung J, Minna JD, et al. Sequential molecular abnormalities are involved in the multistage development of squamous cell carcinoma. Oncogene. 1999. 18:643–650.

12. Zhou X, Kemp BL, Khuri FR, Liu D, Lee JJ, Wu W, et al. Prognostic implications of microsatellite alteration profiles in early-stage non-small cell lung cancer. Clin Cancer Res. 2000. 6:559–565.

13. Smith AL, Hung J, Walker L, Rogers TE, Vuitch F, Lee E, et al. Extensive areas of aneuploidy are present in the respiratory epithelium of lung cancer patients. Br J Cancer. 1996. 73:203–209.

14. Slaughter D, Southwick H, Smejkal W. Field cancerization in oral stratified squamous epithelium: clinical implications of multicentric origin. Cancer. 1953. 6:963–968.

15. Lee JJ, Liu D, Lee JS, Kurie JM, Khuri FR, Ibarguen H, et al. Long-term impact of smoking on lung epithelial proliferation in current and former smokers. J Natl Cancer Inst. 2001. 93:1081–1088.

16. Koga H, Sakisaka S, Ohishi M, Kawaguchi T, Taniguchi E, Sasatomi K, et al. Expression of cyclooxygenase-2 in human hepatocellular carcinoma: relevance to tumor dedifferentiation. Hepatology. 1999. 29:688–696.

17. Shiota G, Okubo M, Noumi T, Noguchi N, Oyama K, Takano Y, et al. Cyclooxygenase-2 expression in hepatocellular carcinoma. Hepatogastroenterology. 1999. 46:407–412.

18. Buckman SY, Gresham A, Hale P, Hruza G, Anast J, Masferrer J, et al. COX-2 expression is induced by UVB exposure in human skin: implications for the development of skin cancer. Carcinogenesis. 1998. 19:723–729.

19. Smalley W, Ray WA, Daugherty J, Griffin MR. Use of nonsteroidal anti-inflammatory drugs and incidence of colorectal cancer : a population-based study. Arch Intern Med. 1999. 159:161–166.

20. Eberhart CE, Coffey RJ, Radhika A, Giardiello FM, Ferrenbach S, DuBois RN. Upregualtion of cyclooxygenase 2 gene expression human colorectal adenomas and adenocarcinomas. Gastroenterology. 1994. 107:1183–1188.

21. Sano H, Kawahito Y, Wilder RL, Hashiramoto A, Mukai S, Kato H, et al. Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res. 1995. 55:3785–3789.

22. Riedl K, Krysan K, Pold M, Dalwadi H, Heuze-Vourc'h N, Dohadwala M, et al. Multifaceted roles of cyclooxygenase-2 in lung cancer. Drug Resist Updat. 2004. 7:169–184.

23. Fridman JS, Lowe SW. Control of apoptosis by p53. Oncogene. 2003. 22:9030–9040.

24. Adimoolam S, Ford JM. p53 and regulation of DNA damage recognition during nucleotide excision repair. DNA Repair (Amst). 2003. 2:947–954.

25. Smith ML, Seo YR. p53 regulation of DNA excision repair pathways. Mutagenesis. 2002. 17:149–156.

26. Pollan M, Varela G, Torres A, de la Torre M, Ludena MD, Ortega MD, et al. Clinical value of p53, c-erbB2, CEA and CA125 regrding relapse, metastasis and death in resectable non-small cell-lung cancer. Int J Cancer. 2003. 107:781–790.

27. Leversha MA, Fielding P, Watson S, Gosney JR, Field JK. Expression of p53, pRB, and p16 in lung tumors: a validation study on tissue microarrays. J Pathol. 2003. 200:610–619.

28. Kwiatkowski DJ, Harpole DH Jr, Godleski J, Herndon JE 2nd, Shieh DB, Richards W, et al. Molecular pathologic substaging in 244 stage I non-small-cell lung cancer patients: clinical implications. J Clin Oncol. 1998. 16:2468–2477.

29. Osaki T, Oyama T, Inoue M, Gu CD, Kodate M, Aikawa M, et al. Molecular biologic markers and micrometastasis in resected non-small cell lung cancer. Prognostic implications. Jpn J Thorac Cardiovasc Surg. 2001. 49:545–551.

30. Geradts J, Fong KM, Zimmerman PV, Maynard R, Minna JD. Correlation of abnormal p16INK4A, and p53 expression with 3p loss of heterozygosity, other genetic abnormalities, and clinical features in 103 primary non-small cell lung cancers. Clin Cancer Res. 1999. 5:791–800.

31. Zereu M, Vinholes JJ, Zettler CG. P53 and Bcl-2 protein expression and its relationship with prognosis in small-cell lung cancer. Clin Lung Cancer. 2003. 4:298–302.

32. Sakuma K, Fujimori T, Hirabayashi K, Terano A. Cyclooxygenase (COX)-2 immunoreactivity and relationship to p53 and Ki-67 expression in colorectal cancer. J Gastroenterol. 1999. 34:189–194.

33. Shattuck-Brandt RL, Lamps LW, Heppner Goss KJ, DuBois RN, Matrisan LM. Differential expression of matrilysin and cyclooxygenase-2 in intestinal and colorectal neoplasms. Mol Carcinog. 1999. 24:177–187.

34. Atula T, Hedstrom J, Ristimaki A, Finne P, Leivo I, Markkanen-Leppanen M, et al. Cyclooxygenase-2 expression in squamous cell carcinoma of the oral cavity and pharynx: association to p53 and clinical outcome. Oncol Rep. 2006. 16:485–490.

35. Laga AC, Zander DS, Cagle PT. Prognostic significance of cyclooxygenase 2 expression in 259 cases of non-small cell lung cancer. Arch Pathol Lab Med. 2005. 129:1113–1117.

36. Khuri FR, Wu H, Lee JJ, Kemp BL, Lotan R, Lippman SM, et al. Cyclooxygenase-2 overexpression is a marker of poor prognosis in stage I non-small cell lung cancer. Clin Cancer Res. 2001. 7:861–867.

37. Lin TS, Chiou SH, Wang LS, Huang HH, Chiang SF, Shih AY, et al. Expression spectra of matrix metalloproteinases in metastatic non-small cell lung cancer. Oncol Rep. 2004. 12:717–723.

38. Jumper C, Cobos E, Lox C. Determination of the serum matrix metalloproteinase-9 (MMP-9) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) in patients with either advanced small-cell lung cancer or non-small-cell lung cancer prior to treatment. Respir Med. 2004. 98:173–177.

39. Yamaguchi NH, Lichtenfels AJ, Demarchi LM, da Silva AP, Garippo AL, Alves VF, et al. COX-2, MMP-9, and Noguchi classification provide additional prognostic information about adenocarcinoma of the lung. A study of 117 patients from Brazil. Am J Clin Pathol. 2004. 121:78–86.

40. Pinto CA, Carvalho PE, Antonangelo L, Garippo A, Da Silva AG, Soares F, et al. Morphometric evaluation of tumor matrix metalloproteinase 9 predicts survival after surgical resection of adenocarcinoma of the lung. Clin Cancer Res. 2003. 9:3098–3104.