Prognostic Significance of MMP2 and MMP9 Functional Promoter Single Nucleotide Polymorphisms in Head and Neck Squamous Cell Carcinoma

Document Type: Original Article


1 HIV and Hepatitis Research Center, Faculty of Laboratorial Sciences, Gerash, Fars, Iran

2 Golestan University of Medical Sciences, Gorgan, Golestan, Iran

3 Cancer Research Institute, Shiraz University of Medical Sciences, Shiraz, Fars, Iran


Matrix metalloproteinases comprise a family of enzyme that is able to degrade components of extra cellular matrix. There are single nucleotide polymorphisms in the promoter regions of several genes with ability to influence cancer susceptibility. The aim of this study was to analyses association between MMP2 and MMP9 promoter polymorphisms and head and neck squamous cell carcinoma occurrence and progression.
Materials and Methods
A case- control study was performed including 80 head and neck squamous cell carcinoma patients and healthy controls for MMP2 and 86 head and neck squamous cell carcinoma patients and 72 healthy controls for MMP9. Blood samples were genotyped for MMP2 and MMP9 using polymerization chain reaction– restriction fragment length polymorphism method (PCR-RFLP). Statistical analysis was performed using SPSS 12.0 software.
Our results showed that distribution of MMP2 genotype between controls and patients was significantly different (χ2= 10.3, P= 0.005). Comparison between CC genotype in HNSCC patients and controls showed that C allele modified the risk of HNSCC progression (OR= 2.6, 95% CI, 1.0046–6.729). The MMP9 genotype distribution among HNSCC patients was significantly different (χ2= 14.56, P= 0.0007). The frequency of TT genotype in HNSCC patients was different from healthy controls and was more common genotype in HNSCC cases (OR= 2.18, 95% CI, 0.7052–6.7854).
Our results suggested an association of the MMP2 and MMP9 SNP with the development of HNSCC. Also, our results showed that MMP, MMP9 genotypes and smoking were related to HNSCC progression.


1. Werb Z. ECM and cell surface proteolysis: regulating cellular ecology. Cell 1997; 91:439–442.

2. Fang S, Jin X, Wang R, Li Y, Guo W, Wang N, et al. Polymorphism in the MMP-1 and MMP-3 promoter an non- small cell lung carcinoma in the north of China. Carcinogenesis 2005; 26:481-486.

3. Zhou G., Zhai Y, Qui W, Dong X, Peng Y, He F. Functional polymorphisms and haplotypes in the promoter of the MMP2 gene are associated with risk of nasopharyngeal carcinoma. Hum Mut 2007; 28:1091-1097.

4. Egeblad M, Werb Z.New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer 2002; 2: 161-174.

5. Ghilardi G, Bionidi ML, Caputo M, Leviti S, Demonti M, Guagnellini E, et al. A single nucleotide polymorphism in the matrix metalloproteinase-3 promoter enhances breast cancer susceptibility. Clin Cancer Res 2002; 11:121-125.

6. Folgueras AR, Pendas AM, Sanchez LM, Lopez-Otin C. Matrix metalloproteinases in cancer: from new functions to improved inhabitation strategies. Int J Dev Biol 2004; 48:411-424.

7. Tower GB, Coon CC, Benbow U, Brinckerhoff CE. Erk 1/2 diffrentially regulates the expression from the IG/2G single nucleotide polymorphism in the MMP1 promoter in melanoma cell. Biochim Biophys Acta 2002; 1586:265-274.

8. Miao X, Yu C, Tan W, Xiong P, Liang G, Lu W, et al. A functional polymorphism in the matrix metalloproteinase -2 gene promoter (-1306C/T) is associated with risk of development but not metastasis of gastric cardia adenocarcinoma. Cancer Res 2003; 63: 3987-3990.

9. Yu C, Zhou Y, Miao X, Xiong P, Tan W, Lin D. Functional haplotypes in the promoter of matrix metalloproteinase -2 predicts risk of the occurrence and metastasis of esophageal cancer. Cancer Res 2004; 64:7622-7628.

10. Huhtala P, Chow LT, Tryggvason K. Structure of the human type IV collagenase gene. J Biol Chem 1990; 265:11077-11082.

11. Price SJ, Greves DR, Watkins H. Identification of novel functional genetic varients in the human matrix metalloproteinase- 2 gene. Role of Sp1 in allele specific transcriptional regulation. J Biol Chem 2001; 276:7549-7558.

12. Vasku A, Goldbergova M, Vacha J.A haplotype constituted of four MMP2 promoter polymorphisms (-1575G/A, -1306C/T, -790T/G and -735C/T) is associated with coronary triple- vessel disease. Matrix Biol 2004; 22:585-591.

13. Joos L, He JQ, Shpherdson MB, Sandfors AJ.The role of matrix metalloproteinase polymorphisms in the rate of decline in lung function. Hum Mol Genet 2002; 11:569-576.

14. Azzam HS, Arand G, Lippman ME, Thomson EW. Association of MMP2 activation potential with metastasic progression in human breast cancer cell lines independent of MMP2 production. J Natl Cancer Inst 2000; 85:1758-1764.

15. Puokolainen H, Paakko P, Turpeenniemi – Hujanen T. Expression of matrix metalloproteinase -9 in head and neck squamous cell carcinoma: a potential marker for prognosis. Clin Cancer Res 2004; 10:3110-3116.

16. Parkin DM, Laara E, Muir CS. Estimates of the worldwide frequency of sixteen major cancers in 1980. Int J Cancer 1988; 41:184–197.

17. Herve' J, LeBoeuf MD. Chemotherapy for head and neck cancer. Otolaryngology 1998.

18. Chambers AF, Matrisian LA. Changing views on the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst 1997; 89: 1260-1270.

19. Kripple P, Langsenlehner U, Renner W, Yazdani- Biuki B, Koppel H, Leithner AC, et al. The 5A/6A polymorphism of matrix metalloproteinase-3 gene promoter and breast cancer. Clin Cancer Res 2004; 10:3518-3520.

20. Motovali-Bashi M, Hojati Z, Hajihoseini S.The role of matrix metalloproteinase-3 functional 5A/6A promoter polymorphism in tumor progression and metastasis of breast cancer. IJB 2008; 6: 45-49.

21. Motovali-Bashi M, Hojati Z, Kouhkan F. Genetic variation in MMP1 promoter region and breast cancer susceptibility. J Sci IRIran 2008; 19:9-14.

22. Kouhkan F, Motovali-Bashi M, Hojati Z. The influence of interstitial Collagenase-1 genotype polymorphism on colorectal cancer risk in Iranian population. Cancer Invest 2008; 26:836-842.

23. Yu C, Zhou Y, Miao X, Xiong P, Tan W, Lin D. Functional haplotypes in the promoter of matrix metalloproteinase -2 predicts risk of the occurrence and metastasis of esophageal cancer. Cancer Res 2004; 64:7622-7628.

24. Lu J, Chua HH, Chen SY, Chen JY, Tsai CH. Regulation of matrix metalloproteinase -1 by Epstein – Barr virus proteins. Cancer Res 2003; 63:256-262.

25. Yoshizaki T, Sato H, Furukawa M. Recent advances in the regulation of matrix metalloproteinase -2 activation:from basic research to clinical implication. Oncol Rep 2002; 9:607-611.

26. Ye S, Eriksson P, Hamsten A, Kurkinen M, E-Humphries S, M- Henney A. Progression of coronary atherosclerosis is associated with a common genetic variation of the human stromelysin-1 promoter which results in reduced gene expression. Biol Chem 1996; 271:13055-13060.

27. Lahman C, Beremann J, Harrison G, Young AR. Matrix metalloproteinase -1 and skin aging in smoker. Lancet 2001; 357:935-936.

28. Miyajima Y, Nakano R, Morimatsu M. Analysis of expression of matrix metalloproteinases-2 and-9 in hypopharyngeal squamous cellcarcinoma by in situ hybridization.Ann Otol Rhinol Laryngol 1995; 104:678–684.

29. Franchi A, Santucci M, Masini E, Sardi I, Paglierani M, Gallo O. Expression of matrix metalloproteinase 1, matrix metalloproteinase 2, and matrix metalloproteinase 9 in carcinoma of the head and neck. Cancer (Phila.) 2002; 95:1902–1910.

30. Scorilas A, Karameris A, Arnogiannaki N, Ardavanis A, Bassilopoulos P, Trangas T, et al. Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourableindicator in node-negative patients. Br J Cancer 2001; 84:1488–1496.