| Objective: Matrix metalloproteinases (MMPs), a family of enzymes depending on Zn2+ and secreted by many cell types, whose basic function is to degrade the extracellular matrix (ECM) and basement membrane (BM), have been involved in the regulation of various cell behaviors with relevance to cancer biology. Genetic variations in the promoter of several MMP genes may influence transcription and expression of MMPs. The single nucleotide polymorphisms (SNPs) in the MMP-1, MMP-3, MMP-7 and MMP-9 promoter regions may modify the transcription and local expression of the corresponding MMP proteins. The aim of this study is to assess the effects of the SNPs, the guanine insertion polymorphism at the -1607bp (-1607 1G/2G) of the MMP-1 promoter, the adenosine deletion polymorphism at the -1171bp (-1171 5A/6A) of the MMP-3 promoter, an A to G transition at the -181bp (-181A/G) of the MMP-7 promoter and an C to T transition at the -1562bp (-1562C/T) of the MMP-9 promoter, on the risk of development and lymphatic metastasis of non-small cell lung carcinoma (NSCLC). Methods: The MMP-1, MMP-3, MMP-7 and MMP-9 SNPs were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis in 243 NSCLC patients and 350 control subjects in North China. Results: The distribution of the MMP-3, MMP-7 and MMP-9 genotypes in NSCLC patients and healthy controls did not significantly deviate from that expected by Hardy-Weinberg equilibrium (all P values are above 0.05). The distribution of the MMP-1 SNP in NSCLC patients was also consistent with Hardy-Weinberg equilibrium (P > 0.05). However, the distribution of the MMP-1 genotypes in healthy controls was not in concordance with Hardy-Weinberg equilibrium (χ~2=12.37, P =0.002). The results showed that the frequency of the MMP-7 -181G allele in NSCLC patients (9.5%) was significantly higher than that in healthy controls (5.0%) (χ2=8.326, P=0.004). Compared to the A/A genotype, the genotypes with the -181G allele (A/G +G/G) significantly increased the susceptibility to NSCLC (sex and age adjusted odds ratio was 2.00, 95%CI=1.23-3.24). However, the overall genotype and allelotype distribution of the MMP-1, MMP-3 and MMP-9 variants in cancer patients and controls was not significantly different (all P values are above 0.05). Stratification analysis found that the MMP-3 gene 5A allele frequency in smoking patients (21.0%) was significantly higher than that in healthy smokers (12.9%) (χ~2=4.81, P=0.03). Therefore, smokers with the MMP-3 5A/6A or 5A/5A genotypesignificantly increased the risk to develop NSCLC (sex and age adjusted OR=2.07, 95%CI=1.13~3.78). However, in either smoking group or non-smoking group, the frequency of the MMP-7 G allele in NSCLC patients (8.8% and 10.3%) is significantly higher than that in healthy controls (3.7% and 5.0%) (χ~2=5.47 and 5.13,P=0.02). Both smoking and non-smoking subjects with the A/G or G/G genotype significantly increased the susceptibility to develop NSCLC, compared to individuals harboring the A/A genotype (the sex and age adjusted odds ratio was 2.40 and 2.53, 95%CI was 1.07-5.42 and 1.19-5.38, respectively). Therefore, interaction between smoking and the -181A/G polymorphism on the risk of NSCLC was not observed. When stratified by pathological types, the frequency of the MMP-7 G allele significantly increased in patients with lung adenocarcinoma (AC) (11.9%) than that in healthy controls (5.1%). Compared to individuals harboring the A/A genotype, the subjects with G/G or G/A genotype significantly increased the risk of lung adenocarcinoma (sex and age adjusted OR was 2.74, 95%CI=1.47-5.13). The NSCLC cases were further stratified according to the status of lymphatic metastasis at the time of diagnosis. The results showed that the MMP-3 5A allele was more common in NSCLC patients with lymphatic metastasis (22.8%) than those without (11.8%) (χ~2=7.31, P=0.007). Compared to individuals harboring the 6A/6A genotype, the subjects with 5A/6A or5A/5A genotype significantly increased the risk of lymphatic metastasis (sex...
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