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Association of Single Nucleotide Polymorphisms in the Promoter of MMP-2 and TIMP-2 Genes with Lung Cancer

Author: JiaShuXiao
Tutor: DingCuiMin
School: Hebei Medical University
Course: Internal Medicine
Keywords: lung cancer MMP-2 TIMP-2 single nucleotide polymorphism susceptibility lymphatic metastasis
CLC: R734.2
Type: Master's thesis
Year: 2009
Downloads: 84
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Abstract

Objective: Matrix metalloproteinases (MMPs) are a family of zinc-dependent endopeptidases, which play important roles in tumor development, invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane (BM), and facilitating angiogenesis. MMP-2, as one of the MMPs family, is especially interesting because of its universal expression and multiple functions. The single nucleotide polymorphisms (SNPs) of MMP-2 may modify the transcriptional activity and protein expression of MMP-2, and further contribute to the development of tumor. In addition, the tissue inhibitor of metalloproteinase-2 (TIMP-2) is the most important endogenous inhibitor of MMP-2. The SNPs in TIMP-2 promoter region have been also associated with tumor development, via modifying the transcriptional activity and further influencing protein expression of TIMP-2 and MMP-2. The aim of the present study was to investigate the association of MMP-2 -735C/T and TIMP-2 -418G/C SNPs with the susceptibility and lymphatic metastasis of Lung Cancer of Han nationality in Hebei province, China.Methods: This case-control study included 370 Lung cancer patients and 436 healthy controls. Patients with histologically confirmed lung cancer were recruited between September 2005 and September 2008, at the Department of Respiratory, Fourth Hospital, Hebei Medical University. All Patients had never undergone radiotherapy or chemotherapy before venous blood was drawn. The controls were selected from cancer-free individuals who conducted medical check-up in Fourth Hospital, Hebei Medical University in the same period.Five milliliter of venous blood from each subject was drawn, and the genomic DNA was extracted by using proteinase K digestion followed by a salting out procedure. Genotypes of the MMP-2 -735C/T and TIMP-2 -418G/C were analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method.Statistical analysis was performed using SPSS11.5 software package. P<0.05 was considered significant for all statistical analyses. Hardy-Weinberg analysis was performed by comparing the observed and expected genotype frequencies in controls using Chi-square test. The age difference between the two groups was analyzed by the t-test. Comparison of the genotype and allelotype distributions in the two groups was performed by means of two-sided contingency tables using Chi-square test. The odds ratio (OR) and 95% confidence Interval (CI) were calculated using an unconditional logistic regression model. Results:1 No significant difference in the MMP-2 -735C/T genotypes or allele distribution was shown between lung cancer patients and healthy controls (P=0.55 and P=0.26). Compared to the C/T+T/T genotypes, the C/C genotype did not significantly modify the risk of lung cancer (OR=1.17, 95%CI=0.86~1.57). However, the C/C genotype may increase the risk of squamous cell carcinoma of lung by stratification analysis according to histological subtypes (OR=1.46, 95%CI=1.00~2.14), and it was not associated with the risk of adenocarcinoma of lung.2 No significant difference in the TIMP-2 -418G/C genotypes or allele distribution was shown between lung cancer patients and healthy controls (P=0.74 and P=0.44). Compared to the G/C+C/C genotypes, the G/G genotype did not significantly modify the risk of lung cancer (OR=0.91, 95%CI=0.67~1.23). The TIMP-2 -418G/C was not associated with the risk of lung cancer when stratified by histological subtypes.3 The proportion of smokers in lung cancer patients (47.8%) was significantly different from that in healthy controls (34.9%) (χ~2=13.95, P=0.00).4 No significant difference was observed between MMP-2 -735C/T and TIMP-2 -418G/C polymorphisms and the risk of lung cancer when stratified by smoking status.5 No significant difference was observed in the frequencies of the MMP-2 -735C/T and TIMP-2 -418G/C genotypes between lymphatic metastasis and non-lymphatic metastasis (P=0.92 and P=0.18). There might be no association between MMP-2 -735C/T and TIMP-2 -418G/C polymorphisms and lymphatic metastasis in lung cancer patients (OR=1.03, 95%CI=0.64~1.65 and OR=0.72, 95%CI=0.44~1.17).6 The combined effect of MMP-2 -735C/T and TIMP-2 -418G/C genotypes showed that the -735C/C﹡-418G/G was the most frequent combined genotype in the population, which was 47.7% in controls. Compared to the -735C/T+T/T﹡-418GG genotype, the other combined genotypes could not modify the risk of lung cancer. No association was observed between the combined genotypes and lymphatic metastasis in lung cancer patients.Conclusions:1 Compared to the T allele, the MMP-2 -735C/C genotype may increase the risk of squamous cell carcinoma of lung, but it was not associated with the risk of adenocarcinoma of lung.2 The TIMP-2 -418G/C was not associated with the risk of lung cancer. The polymorphism had no significant influence on the risk of lung cancer when stratified by histological subtypes.3 Neither MMP-2 -735C/T nor TIMP-2 -418G/C were associated with the risk of lung cancer when stratified by smoking status.4 Neither MMP-2 -735C/T nor TIMP-2 -418G/C were associated with lymphatic metastasis of lung cancer.5 No association was observed between the combined genotypes and the risk of lung cancer.6 No association was observed between the combined genotypes and lymphatic metastasis of lung cancer.

Association of Single Nucleotide Polymorphisms in the Promoter of MMP-2 and TIMP-2 Genes with Lung Cancer

Abstract

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