Yonsei Med J.  2007 Jun;48(3):495-501. 10.3349/ymj.2007.48.3.495.

Expression of Cyclooxygenase-2 and its Relationship to p53 Accumulation in Colorectal Cancers

• Lim SC
• Lee TB
• Choi CH
• Ryu SY
• Kim KJ
• Min YD

• KMID: 724106
• DOI: http://doi.org/10.3349/ymj.2007.48.3.495

Abstract

PURPOSE
Cyclooxygenase (COX)-2 is an inducible isoform responsive to cytokines, mitogens, and growth factors, and is believed to be an important enzyme related to colorectal cancer (CRC). Existing evidence suggests that COX-2 expression is normally suppressed by wild-type p53 but not mutant p53, suggesting that loss of p53 function may result in the induction of COX-2 expression. The aim of this study was to determine the relationship between COX-2 expression and p53 levels in CRC. MATERIALS AND METHODS: Patients with sporadic colorectal adenocarcinoma (n=161) who underwent curative surgery in Chosun University Hospital were enrolled in this study. Expression of COX-2 and p53 proteins was examined by immunohistochemistry in paraffin-embedded cancer tissue blocks, and the relationship between COX-2 and/or p53 expression with clinicopathologic parameters was analyzed. RESUTLS: Expression of COX- 2 was positive in 47.8% of colorectal cancers, and significantly associated with the depth of tumor invasion (p= 0.042). In contrast, p53 was positive in 50.3% of the cases, and was associated with both age (p=0.025) and the depth of tumor invasion (p=0.014). There was no correlation between COX-2 expression and p53 expression (p=0.118). CONCLUSION: These results suggest that COX-2 expression might play an important role in the progression of colorectal cancer. However, COX-2 expression was not associated with mutational p53. Further studies are needed to clarify the regulatory mechanisms governing COX-2 overexpression in colorectal cancers.

Keyword

Cyclooxygenase-2; p53; colorectal cancer; immunohistochemistry

MeSH Terms

Adenocarcinoma/*metabolism/pathology/surgery
Aged
Colorectal Neoplasms/*metabolism/pathology/surgery
Cyclooxygenase 2/*metabolism
Female
Humans
Immunohistochemistry
Male
Middle Aged
Mutation
Tumor Suppressor Protein p53/genetics/*metabolism

Figure

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  Fig. 1 Immunohistochemical staining for COX-2 shown in a representative section. (A) Negative COX-2 staining. (B) Positive staining for COX-2 in colorectal cancer cells.

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  Fig. 2 Immunohistochemical staining for p53 shown in a representative section. (A) Negative staining (less than 10%) for p53. (B) Positive staining for p53.

Reference

1. Boyle P, Zaridze DG, Smans M. Descriptive epidemiology of colorectal cancer. Int J Cancer. 1985. 36:9–18.

2. Annual Report of the Korea Central Cancer Registry 2002. 2002. Ministry of Health and Welfare Republic of Korea.

3. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell. 1990. 61:759–767.

4. Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 1999. 18:7908–7916.

5. Kujubu DA, Fletcher BS, Varnum BC, Lim RW, Herschman HR. TIS10, a phorbol ester tumor promoter-inducible mRNA from Swiss 3T3 cells, encodes a novel prostaglandin synthase/cyclooxygenase homologue. J Biol Chem. 1991. 266:12866–12872.

6. Subbaramaiah K, Dannenberg AJ. Cyclooxygenase2: a molecular target for cancer prevention and treatment. Trends Pharmacol Sci. 2003. 24:96–102.

7. Subbaramaiah K, Altorki N, Chung WJ, Mestre JR, Sampat A, Dannenberg AJ. Inhibition of cyclooxygenase-2 gene expression by p53. J Biol Chem. 1999. 274:10911–10915.

8. Remmele W, Stegner HE. Recommendation for uniform definition of an immunoreactive score (IRS) for immunohistochemical estrogen receptor detection (ER-ICA) in breast cancer tissue. Pathologe. 1987. 8:138–140.

9. Yamauchi T, Watanabe M, Kubota T, Hasegawa H, Ishii Y, Endo T, et al. Cyclooxygenase-2 expression as a new marker for patients with colorectal cancer. Dis Colon Rectum. 2002. 45:98–103.

10. Xiong B, Sun TJ, Hu WD, Cheng FL, Mao M, Zhou YF. Expression of cyclooxygenase-2 in colorectal cancer and its clinical significance. World J Gastroenterol. 2005. 11:1105–1108.

11. Soumaoro LT, Uetake H, Higuchi T, Takagi Y, Enomoto M, Sugihara K. Cyclooxygenase-2 expression: a significant prognostic indicator for patients with colorectal cancer. Clin Cancer Res. 2004. 10:8465–8471.

12. Konno H, Baba M, Shoji T, Ohta M, Suzuki S, Nakamura S. Cyclooxygenase-2 expression correlates with uPAR levels and is responsible for poor prognosis of colorectal cancer. Clin Exp Metastasis. 2002. 19:527–534.

13. Masunaga R, Kohno H, Dhar DK, Ohno S, Shibakita M, Kinugasa S, et al. Cyclooxygenase-2 expression correlates with tumor neovascularization and prognosis in human colorectal carcinoma patients. Clin Cancer Res. 2000. 6:4064–4068.

14. Tomozawa S, Tsuno NH, Sunami E, Hatano K, Kitayama J, Osada T, et al. Cyclooxygenase-2 overexpression correlates with tumor recurrence, especially haematogenous metastasis, of colorectal cancer. Br J Cancer. 2000. 83:324–328.

15. Le Voyer TE, Sigurdson ER, Hanlon AL, Mayer RJ, Macdonald JS, Catalano PJ, et al. Colon cancer survival is associated with increasing number of lymph nodes analyzed: a secondary survey of intergroup trial INT-0089. J Clin Oncol. 2003. 21:2912–2919.

16. Soumaoro LT, Uetake H, Takagi Y, Iida S, Higuchi T, Yasuno M, et al. Coexpression of VEGF-C and Cox-2 in human colorectal cancer and its association with lymph node metastasis. Dis Colon Rectum. 2006. 49:392–398.

17. Bargonetti J, Manfredi JJ. Multiple roles of the tumor suppressor p53. Curr Opin Oncol. 2002. 14:86–91.

18. Levine AJ, Momand J, Finlay CA. The p53 tumor suppressor gene. Nature. 1991. 351:453–456.

19. Harris CC, Hollstein M. Clinical implications of the p53 tumor suppressor gene. N Engl J Med. 1993. 329:1318–1327.

20. Cressey R, Pimpa S, Tontrong W, Watananupong O, Leartprasertsuke N. Expression of cyclooxygenase-2 in colorectal adenocarcinoma is associated with p53 accumulation and hdm2 overexpression. Cancer Lett. 2006. 233:232–239.

21. 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.

22. Liang JT, Huang KC, Jeng YM, Lee PH, Lai HS, Hsu HC. Microvessel density, cyclo-oxygenase 2 expression, K-ras mutation and p53 overexpression in colonic cancer. Br J Surg. 2004. 91:355–361.