Abstract
Purpose
Matrix metalloproteinases (MMPs) play critical roles in cancer development and progression. Nonsynonymous single nucleotide polymorphisms (SNPs) in functional domain of MMP-3 and MMP-9 contribute appreciably to cancer predisposition and aggression. To test this proposition we examined whether six SNPs of the MMP-3 and MMP-9 genes are associated with risk of bladder cancer (BC) in a North Indian population.
Methods
Six SNPs of MMP-3 and MMP-9 were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) in a case–control study including 200 BC patients and 200 age/gender/ethnicity-matched controls.
Results
Increased risk for BC susceptibility was observed in MMP-3 (1171) 5A/5A [P = 0.022; odds ratio (OR), 3.46; 95% confidence interval (CI), 1.20–9.98], MMP-9 (Q279R) QQ (P = 0.048; OR, 1.92; 95%CI, 1.01–3.66), MMP-9 (P574R) PR (P < 0.001; OR, 2.62; 95%CI, 1.71–4.03) and PR + RR (P < 0.001; OR, 2.59; 95%CI, 1.72–3.91) genotypes, and in R allele (P < 0.001; OR, 2.05; 95%CI, 1.47–2.85). Furthermore, significant association between MMP-9 Q279R, P574R polymorphism and smoking was observed in BC risk. Haplotype analysis too revealed significant association with 5A-A-G of MMP-3 haplotype (P = 0.022; OR, 1.99; 95%CI, 1.11–3.60) and with R-R (P = 0.001; OR, 2.00; 95%CI, 1.35–2.97) and Q-R (P < 0.001; OR, 2.97; 95%CI, 1.65–5.37) of MMP-9 haplotype. Genotype 5A/6A of MMP-3-1171 showed borderline risk and high recurrence-free survival in Bacillus Calmette–Guérin (BCG)-treated non-muscle-invasive BC (NMIBC) patients (log-rank P = 0.025).
Conclusion
Our data suggested that MMP-3-1171 5A/5A and MMP-9 (Q279R) QQ, MMP-9 (P574R) PR, PR + RR, and R allele are associated with high risk of BC.
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References
Curran S, Murray GI. Matrix metalloproteinases in tumour invasion and metastasis. J Pathol. 1999;189:300–8.
Stamenkovic I. Matrix metalloproteinases in tumor invasion and metastasis. Semin Cancer Biol. 2000;10:415–33.
Chambers AF, Matrisian LM. Changing views of the role of matrix metalloproteinases in metastasis. J Natl Cancer Inst. 1997;89:1260–70.
Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Natl Rev Cancer 2002;2:161–74.
Wilson CL, Matrisian LM. Matrilysin: an epithelial matrix metalloproteinase with potentially novel functions. Int J Biochem Cell Biol. 1996;28:123–36.
Gerhards S, Jung K, Koenig F, Daniltchenko D, Hauptmann S, Schnorr D, et al. Excretion of matrix metalloproteinases 2 and 9 in urine is associated with a high stage and grade of bladder carcinoma. Urology. 2001;57:675–9.
Gohji K, Fujimoto N, Komiyama T, Fujii A, Ohkawa J, Kamidono S, et al. Elevation of serum levels of matrix metalloproteinase-2 and -3 as new predictors of recurrence in patients with urothelial carcinoma. Cancer. 1996;78:2379–87.
Zinzindohoué F, Lecomte T, Ferraz JM, et al. Prognostic significance of MMP-1 and MMP-3 functional promoter polymorphisms in colorectal cancer. Clin Cancer Res. 2005;11:594–9.
Grieu F, Li WQ, Iacopetta B. Genetic polymorphisms in the MMP-2 and MMP-9 genes and breast cancer phenotype. Breast Cancer Res Treat. 2004;88:197–204.
Colombel M, Soloway M, Akaza H. Epidemiology, staging, grading and risk stratification of bladder cancer. Eur Urol Suppl. 2008;7:618–26.
Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16: 1215.
Shibata N, Ohnuma T, Higashi S, et al. Genetic association between matrix metalloproteinase MMP-9 and MMP-3 polymorphisms and Japanese sporadic Alzheimer’s disease. Neurobiol Aging. 2005;26:1011–4.
Wu J, Zhang L, Luo H, Zhu Z, Zhang C, Hou Y. Association of matrix metalloproteinases-9 gene polymorphisms with genetic susceptibility to esophageal squamous cell carcinoma. DNA Cell Biol. 2008;27:553–7.
Zhang J, Jin X, Fang S, et al. The functional polymorphism in the matrix metalloproteinase-7 promoter increases susceptibility to esophageal squamous cell carcinoma, gastric cardiac adenocarcinoma and non-small cell lung carcinoma. Carcinogenesis. 2005;26:1748–53.
Ye S, Eriksson P, Hamsten A, Kurkinen M, Humphries SE, Henney AM. Progression of coronary atherosclerosis is associated with a common genetic variant of the human stromelysin-1 promoter which results in reduced gene expression. J Biol Chem. 1996;271:13055–60.
Ye S, Watts GF, Mandalia S, Humphries SE, Henney AM. Preliminary report: genetic variation in the human stromelysin promoter is associated with progression of coronary atherosclerosis. Br Heart J. 1995;73:209–15.
Hinoda Y, Okayama N, Takano N, et al. Association of functional polymorphisms of matrix metalloproteinase (MMP)-1 and MMP-3 genes with colorectal cancer. Int J Cancer. 2002;102:526–9.
Ghilardi G, Biondi 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;8:3820–3.
St-Pierre Y, Van Themsche C, Estève PO. Emerging features in the regulation of MMP-9 gene expression for the development of novel molecular targets and therapeutic strategies. Curr Drug Targets Inflamm Allergy. 2003;2:206–15.
Matsumura S, Oue N, Nakayama H, et al. A single nucleotide polymorphism in the MMP-9 promoter affects tumor progression and invasive phenotype of gastric cancer. J Cancer Res Clin Oncol. 2005;131:19–25.
Hu Z, Huo X, Lu D, et al. Functional polymorphisms of matrix metalloproteinase-9 are associated with risk of occurrence and metastasis of lung cancer. Clin Cancer Res. 2005;11:5433–9.
Cotignola J, Reva B, Mitra N, et al. Metalloproteinase-9 (MMP-9) polymorphisms in patients with cutaneous malignant melanoma. BMC Med Genet. 2007;8:10.
Awakura Y, Ito N, Nakamura E, et al. Matrix metalloproteinase-9 polymorphisms and renal cell carcinoma in a Japanese population. Cancer Lett. 2006;241:59–63.
Tang Y, Zhu J, Chen L, Chen L, Zhang S, Lin J. Associations of matrix metalloproteinase-9 protein polymorphisms with lymph node metastasis but not invasion of gastric cancer. Clin Cancer Res. 2008;14:2870–7.
Acknowledgment
The study was funded by Department of Science and Technology, New Delhi, Govt. of India.
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Srivastava, P., Mandhani, A., Kapoor, R. et al. Role of MMP-3 and MMP-9 and Their Haplotypes in Risk of Bladder Cancer in North Indian Cohort. Ann Surg Oncol 17, 3068–3075 (2010). https://doi.org/10.1245/s10434-010-1153-6
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DOI: https://doi.org/10.1245/s10434-010-1153-6