Associations between Single Nucleotide Polymorphisms of COX-2 and MMP-2 Genes and Colorectal Cancer Susceptibility in the Saudi Population

  • Shalaby, Manal Ali (Genetic Engineering and Biotechnology Research Institute (GEBRI), City for Scientific Research and Technology Applications) ;
  • Nounou, Howaida Attia (Department of Medical Biochemistry, Faculty of Medicine, Alexandria University) ;
  • Alanazi, Mohammad Saud (Department of Biochemistry, College of Science, King Khalid University Hospital, King Saud University) ;
  • Alharby, Othman (Department of Internal Medicine, Division of Gastroenterology, King Khalid University Hospital, King Saud University) ;
  • Azzam, Nahla (Department of Internal Medicine, Division of Gastroenterology, King Khalid University Hospital, King Saud University) ;
  • Saeed, Hesham Mahmoud (Institute of Graduate Studies and Research, Department of Bioscience and Technology, Alexandria University)
  • Published : 2014.06.30


Background: It has been reported that COX-2 expression is associated with MMP-2 expression in thyroid and breast cancers, suggesting that MMPs are linked to COX-2-mediated carcinogenesis. Several polymorphisms within the MMP2 promoter region have been reported in cases with oncogenesis and tumor progression, especially in colorectal carcinogenesis. Materials and Methods: This research evaluated risk of association of the SNPs, including genes for COX-2 (AIG transition at +202) and MMP-2 (Crr transition at-1306), with colorectal cancer in 125 patients and 125 healthy controls. Results and Conclusions: Our data confirmed that MMP2 C-1306 T mutations were significantly more common in colon cancer patients than in our control Saudi population; p=O.0121. On the other hand in our study, there was no significant association between genotype distribution ofthe COX2 polymorphism and colorectal cancer; p=0.847. An elevated frequency ofthe mutated genotype in the control group as compared to the patients subjects indeed suggested that this polymorphism could decrease risk in the Saudi population. Our study confirmed that the polymorphisms that could affect the expressions of MMP-2 and COX-2 the colon cancer patients were significantly higher than that in the COX-2 negative group. The frequency of individuals with MMP2 polymorphisms in colon cancer patients was higher than individuals with combination of COX2 and MMP2 polymorphisms. Our study confirmed that individuals who carried the polymorphisms that could affect the expressions ofCOX2 are more susceptible to colon cancer. MMP2 regulatory polymorphisms could be considered as protective; further studies need to confirm the results with more samples and healthy subjects.


  1. Zhang X, Miao X, Tan W, et al (2005). Identification offunctional genetic variants in cyclooxygenase-2 and their association with risk of esophageal cancer. Gastroenterology, 129, 565-76,
  2. Zhao F, Zhu H, Huang M, Yi C, Huang Y (2013), The 765G> C polymorphism in the cyclooxygenase-2 gene and gastric cancer risk: an update by meta-analysis. Asian Pac J Cancer Prev, 15, 2863-8.
  3. Wastson SA, Morriss TM, Robinson G, et al (1995). Inhibition of organ invasion by the matrix metalloproteinase inhibitor BB-94 (batimastat) in two human colon carcinoma metastasis models. Cancer Res, 55, 3629-33.
  4. Tsujii M, Kawano S, DuBois RN (1997). Cyclooxygenase-2 expression in human colon cancer cells increases metastatic potential. Proc Natl Acad Sci USA, 94, 3336-40
  5. Wang X, Fu X, Brown PD, Crimmin MJ (1995). Foffman RM. Matrix metalloproteinase inhibitor BB-94 (batimastat) inhibits human colon tumor growth and spread in a patient-like orthotopic model in a nude mice. Cancer Res, 54, 4726-8.
  6. Wang D, Dubois RN (2006). Prostaglandins and cancer. Gut, 55, 115-22.
  7. Waston SA, Morriss TM, Parsons SL, Steele RJC, Brown PD (1996). Therapeutic effect of matrix metalloproteinase inhibitor, batimastat, in a human colorectal cancer ascites model. Br J Cancer, 74, 1354-8.
  8. Wu HC, Chang CH, Ke HL, et al (2011). Association of cyclooxygenase 2 polymorphic genotypes with prostate cancer in Taiwan. Anticancer Res, 31, 221-25.
  9. Wu CY, Wang CJ, Tseng CC (2005). Helicobacter pylori promote gastric cancer cells invasion through a NF-kappaB and COX-2-mediated pathway, World J Gastroenterol, 11, 3197-203.
  10. Xu E, Lai M, Lv B, et al (2004). A single nucleotide polymorphism in the matrix metalloproteinase-2 promoter is associated with colorectal cancer. Biochem Biophys Res Commun, 324, 999-1003.
  11. Zervos EE, Norman JG, Gower WR, Franz MG, Rosemurgy AS (1997). Matrix metalloproteinase inhibition attenuates human pancreatic cancer growth in vitro and decreases mortality and tumorigenesis in vivo. J Sur Res, 69, 367-71.
  12. Sanger F, Nicklen S, Coulson AR (1977). DNA sequencing with chain terminating inhibitors. Proc Natl Acad Sci U S A, 74, 5463-7,
  13. Papafili A, Hill MR, Brull DJ, McAnulty RJ, Marshall RP, Humphries SE (2002). Common promoter variant in cyclooxygenase-2 represses gene expression: evidence of role in acute-phase inflammatory response. Arterioscler Thromb Vasc BioI, 22, 1631-36.
  14. Price SJ, Greaves DR, Watkins H (2001). Identification of novel, functional genetic variants in the human matrix metalloproteinase-2 gene: role of Sp1 in allele-specific transcriptional regulation. J BioI Chem, 276, 7549-58.
  15. Ruud J, Nilsson A, Ruud L, Wang W, et al (2013). Cancerinduced anorexia in tumor-bearing mice is dependent on cyclooxygenase-1. Brain Behav Immun, 29, 124-35.
  16. Shahedi K, Lindstrom S, Zheng SL, et al (2006). Genetic variation in the COX-2 gene and the association with prostate cancer risk. Int J Cancer, 119, 668-72
  17. Siironen P, Ristimaki A, Nordling S (2004). Expression of COX-2 is increased with age in papillary thyroid cancer. Histopathology, 44, 490-7.
  18. Sivula A, Talvensaari-Mattila A, Lundin J (2005). Association of cyclooxygenase-2 and matrix metalloproteinase-2 expression in human breast cancer. Breast Cancer Res Treat, 89, 215-20,
  19. Song F, Wang L, HuangY, et al (2013). MiR-21 upregulation induced by promoter zone histone acetylation is associated with chemoresistance to gemcitabine and enhanced malignancy of pancreatic cancer cells. Asian Pac J Cancer Prev, 14, 7529-36,
  20. Thiel A, Narko K., Heinonen M, HemmesA, Tomasetto C, Rio MC, Ristimaki A (2012). Inhibition of cyclooxygenase-2 causes regression of gastric adenomas in trefoil factor 1 deficient mice. Int J Cancer, 131, 1032-41.
  21. Tsatsanis C, Androulidaki A, Venihaki M, Margioris AN (2006). Signalling networks regulating cyclooxygenase-2. Int J Biochem Cell BioI, 38, 1654-61.
  22. Markowitz SD (2007). Aspirin and colon cancer-targeting prevention? N Engl J Med, 356, 2195-8.
  23. Kessenbrock K, Plaks V, Werb Z (2010). Matrix metalloproteinases: regulators of the tumor microenvironment. Cell, 141, 52-67.
  24. Lacchini, R, Jacob-Ferreira AL, Luizon MR, et al (2012). Common matrix metalloproteinase 2 gene haplotypes may modulate left ventricular remodelling in hypertensive patients. J Hum Hypertens, 26,171-7.
  25. Langsenlelmer U, Yazdani-Biuki B, Eder T, et al (2006). The cyclooxygenase-2 (PIGS2) 8473T >C polymorphism is associated with breast cancer risk. Clin Cancer Res, 12, 1392-4.
  26. Masferrer JL, Leahy KM, KokiAT, et al (2006). Antiangiogenic and antitumor activities of cyclooxygenase-2 inhibitors. Cancer Res, 60, 1306-11.
  27. Menter DG, Schilsky RL, DuBois RN (2010). Cyclooxygenase-2 and cancer treatment: understanding the risk should be worth the reward. Clin Cancer Res, 16, 1384-90.
  28. Oshima M, Dinchuk JE, Kargman SL (1996). Suppression of intestinal polyposis in Apc delta716 knockout mice by inhibition of cyclooxygenase 2 (COX-2). Cell, 87, 803-9.
  29. Oshima H, Oshima M, Inaba K (2004). Hyperplastic gastric tumours induced by activated macrophages in COX-2/mPGES-1 transgenic mice. EMBO J, 23,1669-78.
  30. Ozhan G, Lochan R, Leathart JBS, Charnley R, Daly AK (2011). Cyclooxygenase-2 polymorphisms and pancreatic cancer susceptibility. Pancreas, 40, 1289-94.
  31. Pereira C, Medeiros RM, Dinis-Ribeiro MJ (2009). Cyclooxygenase polymorphisms in gastric and colorectal carcinogenesis: are conclusive results available? Eur J Gastroenterol Hepatol, 21, 76-91.
  32. Greenhough A, Smartt HJ, Moore AE, et al (2009): The COX-2/PGE2 pathway: key roles in the hallmarks of cancer and adaptation to the tumour microenvironment. Carcinogenesis, 30,377-86.
  33. Eberhart CE, Coffey RJ, Radhika A, et al (1994). Up-regulation of cyclooxygenase 2 gene expression in human colorectal adenomas and adenocarcinomas. Gastroenterology, 107, 1183-8.
  34. Ekambaram P, Lambiv W, Cazzolli R,Ashton W, Honn V (2011). The thromboxane synthase and receptor signaling pathway in cancer: an emerging paradigm in cancer progression and metastasis. Cancer and Metastasis Reviews, 30, 397-408.
  35. Fradet V, Cheng I, Casey G, Witte JS (2009). Dietary omega-3 fatty acids, cyclooxygenase-2 genetic variation, and aggressive prostate cancer risk. Clin Cancer Res, 15, 2559-66.
  36. Gustafsson A, Hansson E, Kressner U, et al (2007). EPl-4 subtype, COX and PPAR gamma receptor expression in colorectal cancer in prediction of disease-specific mortality. Int J Cancer, 121, 232-40.
  37. Gustafsson A, Hansson E, Kressner U, et al (2007). Prostanoid receptor expression in colorectal cancer related to tumor stage, differentiation and progression. Acta Oncol, 56, 1-6.
  38. Hull MA, Ko SC, Hawcroft G (2004). Prostaglandin EP receptors: targets for treatment and prevention of colorectal cancer? Mol Cancer Ther, 3,1031-39.
  39. Hua H, Li M, Luo T, Yin Y, Jiang Y (2011). Matrix metalloproteinases in tumorigenesis: an evolving paradigm. Cellular and Molecular Life Sciences, 68, 3853-68.
  40. Cheng I, Liu X, Plummer SJ, et al (2007). COX2 genetic variation, NSAIDs, and advanced prostate cancer risk. Br J Cancer, 97, 557-61.
  41. Chun S, Surh J (2014). Cancer chemoprevention targeting cox-2 using dietary phytochemicals, in 'Cancer and Inflammation Mechanisms: Chemical, Biological, and Clinical Aspects' (eds Y. Hiraku, S. Kawanishi and H. Ohshima), John Wiley & Sons, Inc., Hoooken, NJ, USA.
  42. Church RD, Fleshman JW, McLeod HL (2003). Cyclooxygenase 2 inhibition in colorectal cancer therapy. Br J Surg, 90, 1055-67.
  43. Chan AT, Ogino S, Fuchs CS (2007). Aspirin and the risk of colorectal cancer in relation to the expression of COX -2. N Engl J Med, 356, 2131-42.
  44. Chulada PC, Thompson MB, Mahler JF (2000). Genetic disruption of Ptgs-l, as well as Ptgs-2, reduces intestinal tumorigenesis in Min mice. Cancer Res, 60, 4705-8.
  45. Decock J, Paridaens R, Ye S (2008). Genetic polymorphisms of matrix metalloproteinases in lung, breast and colorectal cancer. Clin Genet, 73, 197-211.
  46. Dossus L, Kaaks R, Canzian F, et al (2010). PTGS2 and IL6 genetic variation and risk of breast and protate cancer: results from the Breast and Prostate Cancer Cohort Consortium (BPC3). Carcinogenesis, 31, 455-61
  47. Amirian ES, Ittmann MM, Scheurer ME (2011). Associations between arachidonic acid metabolism gene polymorphisms and prostate cancer risk. Prostate, 71, 1382-9.
  48. Asting G, Caren H, Andersson M, Lonnroth C, Lagerstedt K, Lundholm K (2011). COX-2 gene expression in colon cancer tissue related to regulating factors and promoter methylation status. BMC Cancer, 11, 1-10.
  49. Brown JR, DuBois RN (2005). COX-2: a molecular target for colorectal cancer prevention. J Clin Oncol, 23, 2840-55.
  50. Cahlin C, Lonnroth C, Arvidsson A, Nordgren S, Lundholm K (2008). Growth associated proteins in tumor cells and stroma related to disease progression of colon cancer accounting for tumor tissue PGE2 content. Int J Oncol, 32, 909-18.
  51. Callejas NA, Casado M, Diaz-Guerra M (2001). Expression of cyclooxygenase-2 promotes the release of matrix metalloproteinase-2 and -9 in fetal rat hepatocytes. Hepatology, 33, 860-7.
  52. Campa D, Zienolddiny S, Maggini V, et al (2004). Association of a common polymorphism in the cyclooxygenase 2 gene with risk of non-small cell lung cancer. Carcinogenesis, 25, 229-35.
  53. Chun KS, Surh Y (2004). Signal transduction pathways regulating cyclooxygenase-2 expression: potential molecular targets for chemoprevention. Biochem Pharmacal, 68, 1089-1100.

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