Skip to main content

Advertisement

SpringerLink
Log in

Cyclooxygenase-2 Expression Is Associated with Poor Overall Survival of Patients with Gastric Cancer: A Meta-Analysis

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Cyclooxygenase-2 (COX-2) is believed to be involved in gastric carcinogenesis. However, it is still controversial whether COX-2 expression can be regarded as a prognostic factor for gastric cancer patients.

Aim

To obtain a more accurate relationship between COX-2 overexpression and prognosis in gastric cancer by meta-analysis.

Method

Relevant articles published up to May 2013 were searched by use of several keywords in electronic databases. Separate hazard ratio (HR) estimates and 95 % confidence intervals (95 % CI) for COX-2 overexpression and overall survival (OS) and disease-free survival (DFS) with gastric cancer were extracted. Combined HR with 95 % CI was calculated by use of Stata11.0 software to estimate the size of the effect. Publication bias testing and sensitivity analysis were also performed.

Results

A total of 27 studies which included 3,891 gastric cancer patients were combined in the final analysis. Combined results suggested that COX-2 overexpression was associated with an unfavorable OS (HR 1.58, 95 % CI 1.36–1.84) but not DFS (HR 1.15, 95 % CI 0.93–1.43) among patients with gastric cancer. Publication bias was absent. Sensitivity analysis suggested that the results of this meta-analysis were robust.

Conclusions

The results of this meta-analysis suggest that high COX-2 expression may be an independent risk factor for poor OS of patients with gastric cancer. More large prospective studies are now needed to further clarify the prognostic value of COX-2 expression for DFS in gastric cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: Globocan 2008. Int J Cancer. 2010;127:2893–2917.

    Article  CAS  PubMed  Google Scholar 

  2. Herszenyi L, Tulassay Z. Epidemiology of gastrointestinal and liver tumors. Eur Rev Med Pharmacol Sci. 2010;14:249–258.

    PubMed  Google Scholar 

  3. Xing X, Tang YB, Yuan G, et al. The prognostic value of E-cadherin in gastric cancer: a meta-analysis. Int J Cancer. 2013;132:2589–2596.

    Article  CAS  PubMed  Google Scholar 

  4. Zhang QW, Liu L, Chen R, et al. Matrix metalloproteinase-9 as a prognostic factor in gastric cancer: a meta-analysis. Asian Pac J Cancer Prev. 2012;13:2903–2908.

    Article  PubMed  Google Scholar 

  5. Peng L, Zhan P, Zhou Y, et al. Prognostic significance of vascular endothelial growth factor immunohistochemical expression in gastric cancer: a meta-analysis. Mol Biol Rep. 2012;39:9473–9484.

    Article  CAS  PubMed  Google Scholar 

  6. Thiel A, Mrena J, Ristimäki A. Cyclooxygenase-2 and gastric cancer. Cancer Metastasis Rev. 2011;30:387–395.

    Article  CAS  PubMed  Google Scholar 

  7. Wu WK, Sung JJ, Lee CW, et al. Cyclooxygenase-2 in tumorigenesis of gastrointestinal cancers: an update on the molecular mechanisms. Cancer Lett. 2010;295:7–16.

    Article  CAS  PubMed  Google Scholar 

  8. Fujimura T, Ohta T, Oyama K, et al. Role of cyclooxygenase-2 in the carcinogenesis of gastrointestinal tract cancers: a review and report of personal experience. World J Gastroenterol. 2006;12:1336–1345.

    CAS  PubMed  Google Scholar 

  9. Oshima H, Oshima M, Inaba K, et al. Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice. EMBO J. 2004;23:1669–1678.

    Article  CAS  PubMed  Google Scholar 

  10. Thiel A, Narko K, Heinonen M, et al. Inhibition of cyclooxygenase-2 causes regression of gastric adenomas in trefoil factor 1 deficient mice. Int J Cancer. 2012;131:1032–1041.

    Article  CAS  PubMed  Google Scholar 

  11. Jiang H, Wang J, Zhao W. Cox-2 in non-small cell lung cancer: a meta-analysis. Clin Chim Acta. 2013;419:26–32.

    Article  CAS  PubMed  Google Scholar 

  12. Lee JY, Myung SK, Song YS. Prognostic role of cyclooxygenase-2 in epithelial ovarian cancer: a meta-analysis of observational studies. Gynecol Oncol. 2013;129:613–619.

    Article  CAS  PubMed  Google Scholar 

  13. Huang M, Chen Q, Xiao J, et al. Prognostic significance of cyclooxygenase-2 in cervical cancer: a meta-analysis. Int J Cancer. 2013;132:363–373.

    Article  CAS  PubMed  Google Scholar 

  14. Almeida PR, Ferreira FV, Santos CC, et al. Immunoexpression of cyclooxygenase-2 in primary gastric carcinomas and lymph node metastases. World J Gastroenterol. 2012;18:778–784.

    Article  PubMed  Google Scholar 

  15. Joo YE, Rew JS, Seo YH, et al. Cyclooxygenase-2 overexpression correlates with vascular endothelial growth factor expression and tumor angiogenesis in gastric cancer. J Clin Gastroenterol. 2003;37:28–33.

    Article  CAS  PubMed  Google Scholar 

  16. Tang H, Wang J, Bai F, et al. Positive correlation of osteopontin, cyclooxygenase-2 and vascular endothelial growth factor in gastric cancer. Cancer Invest. 2008;26:60–67.

    Article  CAS  PubMed  Google Scholar 

  17. Zhang X, Wu Q, Gan L, et al. Reduced group IVA phospholipase A2 expression is associated with unfavorable outcome for patients with gastric cancer. Med Oncol. 2013;30:454.

    Article  PubMed  Google Scholar 

  18. Jiang H, Qiao XL, Huang FY. Expressions and clinical significance of Smad4 and Cox-2 in gastric cancer. J Clin Med Pract. 2012;16:30–33.

    Google Scholar 

  19. Fanelli MF, Chinen LT, Begnami MD, et al. The influence of transforming growth factor-a, cyclooxygenase-2, matrix metalloproteinase (MMP)-7, MMP-9 and CXCR4 proteins involved in epithelial–mesenchymal transition on overall survival of patients with gastric cancer. Histopathology. 2012;61:153–161.

    Article  PubMed  Google Scholar 

  20. Gou HF, Chen XC, Zhu J, et al. Expressions of COX-2 and VEGF-C in gastric cancer: correlations with lymphangiogenesis and prognostic implications. J Exp Clin Cancer Res. 2011;30:14.

    Article  CAS  PubMed  Google Scholar 

  21. Zhang C, Wang XQ, Xu C, et al. Expression of cyr-61 and cox-2 in gastric carcinoma and its clinical significance. J China Med Univ. 2011;40:744–748.

    CAS  Google Scholar 

  22. Sun GY, Luo DH, Wu JS, et al. The expression of NICD and COX-2 in gastric carcinoma tissues and its clinical biological significance. J Med Res. 2011;40:61–66.

    Google Scholar 

  23. Tatsuwaki H, Tanigawa T, Watanabe T, et al. Reduction of 15-hydroxyprostaglandin dehydrogenase expression is an independent predictor of poor survival associated with enhanced cell proliferation in gastric adenocarcinoma. Cancer Sci. 2010;101:550–558.

    Article  CAS  PubMed  Google Scholar 

  24. Mrena J, Wiksten JP, Kokkola A, et al. COX-2 is associated with proliferation and apoptosis markers and serves as an independent prognostic factor in gastric cancer. Tumour Biol. 2010;31:1–7.

    Article  CAS  PubMed  Google Scholar 

  25. Li Y, Tan BB, Fan LQ, et al. Expression of COX-2, survivin in regional lymph node metastases of gastric carcinoma and the correlation with prognosis. Hepatogastroenterology. 2010;57:1435–1441.

    CAS  PubMed  Google Scholar 

  26. Zhai JH, Li N, Zhang L, et al. Expression of P16, C-MYC and COX-2 in gastric carcinoma and relationship with the prognosis of patients. J Zhejiang Coll Tradit Chin Med. 2009;33:321–322.

    CAS  Google Scholar 

  27. Yamac D, Ayyildiz T, Coskun U, et al. Cyclooxygenase-2 expression and its association with angiogenesis, Helicobacter pylori, and clinicopathologic characteristics of gastric carcinoma. Pathol Res Pract. 2008;204:527–536.

    Article  PubMed  Google Scholar 

  28. Ye SC, Wang JY, Yuan GZ, et al. Expression of COX-2 and P-gp and its prognosis in gastric carcinoma. Chin Gen Pract. 2008;11:291–294.

    CAS  Google Scholar 

  29. Lazar D, Taban S, Ardeleanu C, et al. Immunohistochemical expression of the cyclooxygenase-2 (COX-2) in gastric cancer. The correlations with the tumor angiogenesis and patients’ survival. Rom J Morphol Embryol. 2008;49:371–379.

    PubMed  Google Scholar 

  30. Kolev Y, Uetake H, Takagi Y, et al. Lactate dehydrogenase-5 (LDH-5) expression in human gastric cancer: association with hypoxia-inducible factor (HIF-1alpha) pathway, angiogenic factors production and poor prognosis. Ann Surg Oncol. 2008;15:2336–2344.

    Article  PubMed  Google Scholar 

  31. Da MX, Wu XT, Wang J, et al. Expression of cyclooxygenase-2 and vascular endothelial growth factor-C correlates with lymphangiogenesis and lymphatic invasion in human gastric cancer. Arch Med Res. 2008;39:92–99.

    Article  CAS  PubMed  Google Scholar 

  32. Gudis K, Tatsuguchi A, Wada K, et al. Clinical significance of prostaglandin E synthase expression in gastric cancer tissue. Hum Pathol. 2007;38:1826–1835.

    Article  CAS  PubMed  Google Scholar 

  33. Li M, Liu W, Zhu YF, et al. Correlation of COX-2 and K-ras expression to clinical outcome in gastric cancer. Acta Oncol. 2006;45:1115–1119.

    Article  CAS  PubMed  Google Scholar 

  34. Joo YE, Chung IJ, Park YK, et al. Expression of cyclooxygenase-2, p53 and Ki-67 in gastric cancer. J Korean Med Sci. 2006;21:871–876.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Linder N, Haglund C, Lundin M, et al. Decreased xanthine oxidoreductase is a predictor of poor prognosis in early-stage gastric cancer. J Clin Pathol. 2006;59:965–971.

    Article  CAS  PubMed  Google Scholar 

  36. Yu JR, Wu YJ, Qin Q, et al. Expression of cyclooxygenase-2 in gastric cancer and its relation to liver metastasis and long-term prognosis. World J Gastroenterol. 2005;11:4908–4911.

    CAS  PubMed  Google Scholar 

  37. Okano H, Shinohara H, Miyamoto A, et al. Concomitant overexpression of cyclooxygenase-2 in HER-2-positive on Smad4-reduced human gastric carcinomas is associated with a poor patient outcome. Clin Cancer Res. 2004;10:6938–6945.

    Article  CAS  PubMed  Google Scholar 

  38. Shi H, Xu JM, Hu NZ, et al. Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma. World J Gastroenterol. 2003;9:1421–1426.

    CAS  PubMed  Google Scholar 

  39. Joo YE, Oh WT, Rew JS, et al. Cyclooxygenase-2 expression is associated with well-differentiated and intestinal-type pathways in gastric carcinogenesis. Digestion. 2002;66:222–229.

    Article  CAS  PubMed  Google Scholar 

  40. Leung WK, To KF, Ng YP, et al. Association between cyclo-oxygenase-2 overexpression and missense p53 mutations in gastric cancer. Br J Cancer. 2001;84:335–339.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. Lee TL, Leung WK, Lau JY, et al. Inverse association between cyclooxygenase-2 overexpression and microsatellite instability in gastric cancer. Cancer Lett. 2001;168:133–140.

    Article  CAS  PubMed  Google Scholar 

  42. Chen CN, Sung CT, Lin MT, et al. Clinicopathologic association of cyclooxygenase 1 and cyclooxygenase 2 expression in gastric adenocarcinoma. Ann Surg. 2001;233:183–188.

    Article  CAS  PubMed  Google Scholar 

  43. Lim HY, Joo HJ, Choi JH, et al. Increased expression of cyclooxygenase-2 protein in human gastric carcinoma. Clin Cancer Res. 2000;6:519–525.

    CAS  PubMed  Google Scholar 

  44. Nordmann AJ, Kasenda B, Briel M. Meta-analyses: what they can and cannot do. Swiss Med Wkly. 2012;142:w13518.

    PubMed  Google Scholar 

  45. McShane LM, Altman DG, Sauerbrei W. Reporting recommendations for tumor marker prognostic studies (remark). Exp Oncol. 2006;28:99–105.

    CAS  PubMed  Google Scholar 

  46. Chen M, Cai E, Huang J, et al. Prognostic value of vascular endothelial growth factor expression in patients with esophageal cancer: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev. 2012;21:1126–1134.

    Article  CAS  PubMed  Google Scholar 

  47. Tierney JF, Stewart LA, Ghersi D, Burdett S, Sydes MR. Practical methods for incorporating summary time-to-event data into meta-analysis. Trials. 2007;7:8–16.

    Google Scholar 

  48. Parmar MK, Torri V, Stewart L. Extracting summary statistics to perform meta-analyses of the published literature for survival endpoints. Stat Med. 1998;17:2815–2834.

    Article  CAS  PubMed  Google Scholar 

  49. Egger M, Smith GD, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–634.

    Article  CAS  PubMed  Google Scholar 

  50. Zhao HC, Qin R, Chen XX, et al. Microvessel density is a prognostic marker of human gastric cancer. World J Gastroenterol. 2006;12:7598–7603.

    PubMed  Google Scholar 

  51. Han SL, Tang HJ, Hua YW, et al. Expression of COX-2 in stomach cancers and its relation to their biological features. Dig Surg. 2003;20:107–114.

    Article  CAS  PubMed  Google Scholar 

  52. Al-Moundhri MS, Al-Hadabi I, Al-Mawaly K, et al. Prognostic significance of cyclooxygenase-2, epidermal growth factor receptor 1, and microvascular density in gastric cancer. Med Oncol. 2012;29:1739–1747.

    Article  CAS  PubMed  Google Scholar 

  53. Dicken BJ, Graham K, Hamilton SM, et al. Lymphovascular invasion is associated with poor survival in gastric cancer: an application of gene-expression and tissue array techniques. Ann Surg. 2006;243:64–73.

    Article  PubMed  Google Scholar 

  54. Vidal O, Soriano-Izquierdo A, Pera M, et al. Positive VEGF immunostaining independently predicts poor prognosis in curatively resected gastric cancer patients: results of a study assessing a panel of angiogenic markers. J Gastrointest Surg. 2008;12:1005–1014.

    Article  PubMed  Google Scholar 

  55. Mrena J, Wiksten JP, Thiel A, et al. Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res. 2005;11:7362–7368.

    Article  CAS  PubMed  Google Scholar 

  56. Mrena J, Wiksten JP, Nordling S, et al. MMP-2 but not MMP-9 associated with COX-2 and survival in gastric cancer. J Clin Pathol. 2006;59:618–623.

    Article  CAS  PubMed  Google Scholar 

  57. Kolev Y, Uetake H, Iida S, et al. Prognostic significance of VEGF expression in correlation with COX-2, microvessel density, and clinicopathological characteristics in human gastric carcinoma. Ann Surg Oncol. 2007;14:2738–2747.

    Article  PubMed  Google Scholar 

  58. Jamieson NB, Carter CR, McKay CJ, et al. Tissue biomarkers for prognosis in pancreatic ductal adenocarcinoma: a systematic review and meta-analysis. Clin Cancer Res. 2011;17:3316–3331.

    Article  CAS  PubMed  Google Scholar 

  59. Li L, Zhao J, Wu Z, et al. Meta-analysis: clinicopathological and prognostic significance of cyclooxygenase-2 expression on oesophageal squamous cell carcinoma. Aliment Pharmacol Ther. 2009;30:589–596.

    Article  CAS  PubMed  Google Scholar 

  60. Peng L, Zhou Y, Wang Y, et al. Prognostic significance of COX-2 immunohistochemical expression in colorectal cancer: a meta-analysis of the literature. PLoS ONE. 2013;8:e58891.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  61. Claesson-Welsh L, Welsh M. VEGFA and tumour angiogenesis. J Intern Med. 2013;273:114–127.

    Article  CAS  PubMed  Google Scholar 

  62. Tatsuguchi A, Matsui K, Shinji Y, et al. Cyclooxygenase-2 expression correlates with angiogenesis and apoptosis in gastric cancer tissue. Hum Pathol. 2004;35:488–495.

    Article  CAS  PubMed  Google Scholar 

  63. Sun WH, Sun YL, Fang RN, et al. Expression of cyclooxygenase-2 and matrix metalloproteinase-9 in gastric carcinoma and its correlation with angiogenesis. Jpn J Clin Oncol. 2005;35:707–713.

    Article  PubMed  Google Scholar 

  64. Lukaszewicz-Zając M, Mroczko B, Szmitkowski M. Gastric cancer—the role of matrix metalloproteinases in tumor progression. Clin Chim Acta. 2011;412:1725–1730.

    Article  PubMed  Google Scholar 

  65. Gamba CA, Swetter SM, Stefanick ML, et al. Aspirin is associated with lower melanoma risk among postmenopausal Caucasian women: the women’s health initiative. Cancer. 2013;119:1562–1569.

    Article  CAS  PubMed  Google Scholar 

  66. Gammon MD, Terry MB, Arber N, et al. Nonsteroidal anti-inflammatory drug use associated with reduced incidence of adenocarcinomas of the esophagus and gastric cardia that overexpress cyclin D1: a population-based study. Cancer Epidemiol Biomarkers Prev. 2004;13:34–39.

    Article  CAS  PubMed  Google Scholar 

  67. Yang P, Zhou Y, Chen B, et al. Aspirin use and the risk of gastric cancer: a meta-analysis. Dig Dis Sci. 2010;55:1533–1539.

    Article  CAS  PubMed  Google Scholar 

  68. Yu J, Tang BD, Leung WK, et al. Different cell kinetic changes in rat stomach cancer after treatment with celecoxib or indomethacin: implications on chemoprevention. World J Gastroenterol. 2005;11:41–45.

    CAS  PubMed  Google Scholar 

  69. Liu H, Huang P, Xu X, et al. Anticancer effect of celecoxibvia COX-2 dependent and independent mechanisms in human gastric cancers cells. Dig Dis Sci. 2009;54:1418–1424.

    Article  CAS  PubMed  Google Scholar 

  70. Keller JJ, Giardiello FM. Chemoprevention strategies using NSAIDs and COX-2 inhibitors. Cancer Biol Ther. 2003;2:140–149.

    Article  Google Scholar 

  71. Russo A, Bazan V, Migliavacca M, et al. Prognostic significance of DNA ploidy, S-phase fraction, and tissue levels of aspartic, cysteine, and serine proteases in operable gastric carcinoma. Clin Cancer Res. 2000;6:178–184.

    CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None.

Author information

Authors and Affiliations

  1. Department of Epidemiology and Biostatistics, School of Public Health, Anhui Medical University, 69 Meishan Road, Hefei, 230032, Anhui Province, China

    Jian Song, Hong Su, Yang-yang Zhou & Liang-liang Guo

Authors
  1. Jian Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yang-yang Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Liang-liang Guo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hong Su.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Song, J., Su, H., Zhou, Yy. et al. Cyclooxygenase-2 Expression Is Associated with Poor Overall Survival of Patients with Gastric Cancer: A Meta-Analysis. Dig Dis Sci 59, 436–445 (2014). https://doi.org/10.1007/s10620-013-2917-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-013-2917-1

Keywords

Search

Navigation