A functional polymorphism in the matrix metal lop roteinase-1 gene promoter is associated with susceptibility and aggressiveness of head and neck cancer

Matrix metalloproteinases (MMPs) play an important role in several steps of cancer development. A single guanine insertion polymorphism (2G) in the MMP1 promoter sequence at -1,607 creates an Ets binding site and thus results in enhancing transcriptional activity. This study aimed to evaluate the contribution of this 2G polymorphism on susceptibility and aggressiveness of HNSCC. A panel of HNSCC cell lines and peritumoral fibroblasts were examined for the MMPI genotypes and expression levels. Genomic DNA was extracted from peripheral blood of 300 patients with newly diagnosed HNSCC and from 300 age- and gender-matched cancer-free controls. Genotyping was carried out using a PCR-RFLP assay. The levels of MMPI mRNA expression were evaluated by the quantitative RT-PCR and a correlation with different genotype was determined. Odds ratio (OR) for cancer risk were calculated using multivariate logistic regression. In addition, a correlation between the 2G/2G genotype and clinicopathological parameters was examined. Eleven out of 18 HNSCC cell lines showed the 2G/2G genotype (61%) and only 1 cell line had the 1G/1G genotype (5.6%). Cell lines with the 2G/2G genotype expressed significantly higher mean MMPI mRNA level than those with other genotypes. In clinical model, subjects carrying the homozygous 2G/2G, genotype had a higher risk of head and neck cancer compared with subjects with other genotypes (adjusted OR: 2.28; 95% CI: 1.58-3.27), controlling for major confounders. A correlation between promoter polymorphisms and the levels of MMPI expression in cancer tissues was found, and this 2G/2G genotype was correlated with the adverse clinicopathological parameters. Finally, the highest level of MMPI enhancement was demonstrated in the coculture of tumor cells and peritumoral fibroblasts of 2G homozygotes. These findings suggest that the presence of 2113 polymorphism at the MMPI promoter is associated with the development and progression of HNSCC. (c) 2005 Wiley-Liss, Inc.