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International Journal of Clinical and Experimental Medicine logoLink to International Journal of Clinical and Experimental Medicine
. 2015 Oct 15;8(10):17096–17101.

Meta-analysis of association of the matrix metalloproteinase 2 (-735 C/T) polymorphism with cancer risk

Su Kang Kim 1,*, Sang Wook Kang 1,*, Hae Jeong Park 1, Ju Yeon Ban 2, Chung-Hun Oh 2, Joo-Ho Chung 1, In-Hwan Oh 3, Kyu Bong Cho 4, Min-Su Park 5
PMCID: PMC4694202  PMID: 26770302

Abstract

The association between matrix metalloproteinase 2 (MMP2) gene polymorphisms and cancer risk has been investigated in many published studies; however, the currently available results are inconclusive. Therefore, we performed a meta-analysis to provide conclusive evidence for an association between the MMP2 polymorphism (-735 C/T) and cancer risk. Sixteen case-control studies with 11792 individuals were included in this meta-analysis. The odds ratio (OR) and 95% confidence interval (95% CI) were used to investigate the strength of the association. Overall, the MMP2 polymorphism (-735 C/T) was not associated with cancer risk in any of the models. However, the subgroup analysis revealed that dominant model (C/T+T/T vs. C/C: OR=1.24, 95% CI=1.01-1.53) and codominant 1 model (C/T vs. C/C: OR=1.30, 95% CI=1.05-1.62) were significantly associated with cancer risk in the Caucasian population. In conclusion, our meta-analysis indicated that the MMP2 polymorphism (-735 C/T) might be genetic risk factor for the carcinogenesis in Caucasians. However, more studies with a larger sample size are needed to provide more precise evidence.

Keywords: Matrix metalloproteinase 2, polymorphism, cancer, meta-analysis

Introduction

Cancer is a broad group of diseases characterized by unregulated cell growth and invade healthy cells in human. The cancer may invade or spread to other parts of the body. Cancer invasion and metastasis involve the detachment of tumor cells from the primary tumor, invasion through the basement membrane, intravasation into the circulatory system, extravasation at a distant site, and outgrowth of a secondary tumor [1]. The remodeling of extracellular matrix by matrix metalloproteinase (MMPs) is important for each step of cancer progression [2].

MMPs are a family of Zn2+-dependent endopeptidases. They are essential for tumor growth, angiogenesis, and metastatic processes [3-5]. Among secreted MMPs, MMP2 plays a significant role in cancer invasion and metastasis by degrading extracellular matrix. In addition, it plays an important role in cell proliferation, apoptosis and immune surveillance [2,6-8]. MMP2 is expressed in normal healthy tissues. Expanding studies have shown that the expression of MMP2 is up-regulated in several types of cancers [9-11]. It suggested that MMP2 may play a significant role in the development and progression of cancers.

The MMP2 gene is located on the long arm of chromosome 16 between positions 13 and 21. Several single nucleotide polymorphisms (SNP) in the promoter region of MMP2 gene have recently been identified. Especially, MMP2 polymorphism (-735 C/T) in the promoter region has been characterized functionally [12,13].

Up to now, number of studies have been conducted to evaluate the association between MMP2 promoter polymorphism and risk of different types of cancers in diverse populations including breast cancer, bladder cancer, esophageal cancer, lung cancer, hepatocellular carcinoma, prostate cancer and etc. However, the results from the published studies remain conflicting rather than conclusive. Therefore, we performed a meta-analysis on all eligible case-control studies to clarify the association between MMP2 polymorphism (-735 C/T) and susceptibility to cancer.

Materials and methods

Search strategy

Case and control studies were identified by searching in PubMed, Medline, and Google, up to January 2015 without language restrictions. Relevant studies were identified using the terms: “matrix metalloproteinase2 or MMP2 AND “polymorphism or polymorphisms or variant” AND-735 AND “cancer or carcinoma”. The study was restricted to human. Additional studies were searched by hand search of original or review articles references. If data or data subsets were published in more than one article, only the genetic data from the larger sample size were included.

Inclusion criteria

Studies were included if they met the following criteria: (1) evaluated the association between the MMP2 polymorphism (-735 C/T) and cancer; (2) used a case-control study design; (3) contained sufficient published data for the estimation of an odds ratio (OR) with a 95% confidence interval (CI).

Data extraction

The two investigators independently extracted data and reached consensus on all of the items. If the two investigators generated different results, they would check the data again and had a discussion to come to an agreement. Data extracted from the selected articles including the first author’s name, year of publication, country of origin, ethnicity of study population, number of cases and controls and genotype frequency of MMP2 polymorphism (-735 C/T). The ethnicity was divided into Asian and Caucasian population.

Statistical analysis

The chi-square test was used to calculate the Hardy-Weinberg equilibrium (HWE) in the control group. And meta-analysis was performed using the comprehensive meta-analysis software (Corporation, NJ, USA). The pooled p value, OR and 95% CI were used to investigate association between risk of cancer and MMP2 polymorphism (-735 C/T). The random effects model or the fixed effects model was used. OR with the corresponding 95% CI was calculated for the codominant 1 model (C/C vs. C/T), codominant 2 model (C/C vs. T/T), dominant model (C/C vs. C/T+T/T), recessive model (C/C+C/T vs. T/T), and allele (C vs. T), respectively [14,15]. The P-value less than 0.05 was regarded as statistically significant. A χ 2-test-based Q statistic test was performed to assess heterogeneity of the study. We also determined the effect of heterogeneity using I2 test. The random-effects Mantel-Haenszel method was adopted if the result of the Q test was a P-value less than 0.05 or a I2 statistic was larger than 50%, which indicated the statistically significant heterogeneity between the studies. Otherwise, the fixed-effects Mantel-Haenszel method was adopted. To test for publication bias, the Egger’s regression was applied.

Results

Study characteristics

Our meta-analysis of present study included sixteen studies, as shown in Table 1, comprising 16 articles including 5487 cancer patients and 6305 control subjects were ultimately selected [16-31]. The characteristics of the selected studies in terms of MMP2-735 C/T polymorphism and cancer type are summarized in Table 1. The types of various cancers included were; lung cancer (3), head and neck cancer (2), esophageal cancer (2), hepatocellular carcinoma (1), gastric cancer (1), ovarian cancer (1), colorectal cancer. (1), gallbladder cancer (1), prostate cancer (1), bladder cancer (1), breast cancer (1), and lymphoma (1).

Table 1.

Characteristics of eligible studies included in the meta-analysis

Study Cancer type Country Ethnicity Year Genotyping method Case/control Case Control HWE
CC CT TT CC CT TT
Rollin et al. [16] Lung cancer French Caucasian 2007 PCR-RFLP 89/90 69 18 2 67 21 2 0.82
Zhou et al. [17] Lung cancer China Asian 2004 PCR-RFLP 770/777 506 230 34 425 313 39 0.05
Zhou et al. [18] Head & neck cancer China Asian 2007 Sequencing 580/478 397 159 24 281 167 30 0.44
Ozgen et al. [19] Head & neck cancer Turkey Caucasian 2008 PCR-RFLP 42/147 23 19 0 99 51 7 0.89
Yu et al. [20] Esophageal cancer China Asian 2004 PCR-RFLP 527/777 323 179 25 425 313 39 0.05
Sun et al. [21] Esophageal cancer China Asian 2009 PCR-RFLP 335/624 222 100 13 408 187 29 0.21
Zhai et al. [22] Hepatocellular carcinoma China Asian 2007 Sequencing 431/478 229 167 35 281 167 30 0.44
Sun et al. [15] Gastric cancer China Asian 2009 PCR-RFLP 257/624 185 63 9 408 187 29 0.21
Li et al. [23] Ovarian cancer China Asian 2008 PCR-RFLP 246/324 164 69 13 181 127 16 0.29
Park et al. [24] Colorectcal cancer Korea Asian 2010 PCR-RFLP 333/318 180 128 25 189 110 19 0.58
Sharma et al. [25] Gallbladder cancer India Asian 2012 PCR-RFLP 410/230 290 112 8 188 40 2 0.94
Gonzalez et al. [26] Lung cancer Spain Caucasian 2012 PCR-RFLP 879/803 596 206 14 465 125 20 0.002
Srivastava et al. [27] Prostate cancer India Asian 2012 PCR-RFLP 190/200 132 50 8 135 60 5 0.58
Srivastava et al. [28] Bladder cancer India Asian 2013 PCR-RFLP 200/200 122 69 9 135 60 5 0.58
Yari et al. [29] Breast cancer Iran Asian 2014 PCR-RFLP 98/135 70 28 0 80 52 3 0.09
Mahmoud et al. [14] Lymphoma Egypt Caucasian 2014 PCR-RFLP 100/100 70 23 7 85 15 0 0.42
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Quantitative synthesis

Table 2 shows the results from the overall meta-analysis. The sixteen studies were analyzed in meta-analysis. And Figure 1 shows OR and 95% CI of individual and pooled data for the MMP2-735 C/T polymorphism and susceptibility of cancer.

Table 2.

Overall analysis between MMP2 polymorphism (-735 C/T) and susceptibility of cancer

Genetic comparison Population OR (95% CI) P Heterogeneity Model
P I2
C vs. T All 0.98 (0.85-1.14) 0.80 <0.001 76.74 Random
Asian 0.93 (0.79-1.09) 0.37 <0.001 77.89 Random
Caucasian 1.26 (0.83-1.91) 0.27 0.03 65.60 Random
C/C+C/T vs. T/T All 0.95 (0.79-1.14) 0.58 0.29 14.40 Fixed
Asian 0.99 (0.81-1.20) 0.91 0.56 <0.001 Fixed
Caucasian 0.62 (0.34-1.16) 0.14 0.12 48.90 Fixed
C/C vs. C/T+T/T All 0.97 (0.81-1.16) 0.71 <0.001 78.20 Random
Asian 0.90 (0.74-1.09) 0.28 <0.001 79.26 Random
Caucasian 1.24 (1.01-1.53) 0.040 0.17 40.72 Fixed
C/C vs. C/T All 0.99 (0.80-1.15) 0.63 <0.001 76.41 Random
Asian 0.89 (0.73-1.07) 0.22 <0.001 76.84 Random
Caucasian 1.30 (1.05-1.62) 0.015 0.42 <0.001 Fixed
C/C vs. T/T All 0.90 (0.75-1.09) 0.29 0.12 30.71 Fixed
Asian 0.93 (0.76-1.14) 0.48 0.20 25.38 Fixed
Caucasian 0.66 (0.35-1.23) 0.19 0.12 48.76 Fixed
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OR, odds ratio; Bold numbers indicant significant association with risk of cancer.

Figure 1.

Figure 1

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Odds ratio and 95% CI of individual and pooled data for the MMP2 polymorphism (-735 C/T) and susceptibility of cancer. A: C allele vs. T allele; B: C/C genotype + C/T genotype vs. T/T genotype; C: C/C genotype vs. C/T genotype + T/T genotype.

The T allele and genotypes including T allele of the MMP2-735 C/T polymorphism was not associated with susceptibility for cancer when compared with the C allele and genotype including C allele in the overall population (P>0.05, Table 2 and Figure 1A-C).

When stratified for ethnicity, T/T and/or C/T genotypes, and T allele did not show any significant association with cancer in the Asian population (P>0.05). However, there was significant association with risk of cancer in the Caucasian population. When the C/T genotype+T/T genotype of MMP2-735 C/T polymorphism was compared with C/C genotype (dominant model), there was a significant association with risk of cancers in the Caucasian population (fixed model, OR=1.24, 95% CI=1.01-1.53, P=0.040, heterogeneity=40.72, Table 2). And in the co-dominant 1 model, frequency of C/T genotype in the Caucasian population also showed significant association compared C/C genotype (fixed model, OR=1.30, 95% CI=1.05-1.62, P=0.015, heterogeneity <0.001). Although the study by Gonzalez, et al. 2012 was observed that HWE in the control group was not consistent (P=0.002), a publication bias was not observed (Egger’s regression P=0.87 in the codominant 1 model and Egger’s regression P=0.65 in the dominant model).

Discussion

MMP2 is involved in the proteolysis of the extracellular matrix, making it a key enzyme in cancer initiation and progression. MMP2 can regulate the tumor microenvironment and thus, plays a critical role in both tumor invasion and metastasis. Also, numerous studies have shown poor prognosis in tumors overexpressing MMP2 [10,11].

The MMP2-735 C/T polymorphism is located in the promoter region, appears to be closely associated with expression of MMP2, and is involved in the process of tumor progression. The association between MMP2-735 C/T polymorphism and cancer risk has been investigated in a broad range of studies with either a relatively small or larger sample size for the different populations. In previous meta-analysis studies, the MMP2-735 C/T polymorphism was reported to be associated with increased cancer risk [32]. Also, it was reported that MMP2-735 C/T polymorphism was associated with lung cancer risk, and patients with high MMP2 expression levels have poor overall survival compared with those with low MMP2 expression levels [33]. However, because of the difference in the number of participants and genetic background, the evidence provided by each study is not sufficient enough to draw a convincing conclusion. We conducted an up-dated meta-analysis including with 5487 cases and 6305 controls from 16 case-control studies to evaluate the association between MMP2-735 C/T polymorphism and the cancer risk.

In our study, we examined the association of MMP2-735 C/T polymorphism with the risk for cancer by meta-analysis. We found that this polymorphism was related with the increased risk of cancer. Subgroup analysis by ethnicity demonstrated that the MMP2-735 C/T polymorphisms were associated with increased cancer risk among the Caucasian population under the dominant and co-dominant 1 model.

We also have to mention the importance of heterogeneity. The heterogeneity was found in some comparisons in our meta-analysis. To get more full and accurate detail of the precious date, we used random-effects model or fixed model. The results were stable with the sensitivity analysis which did not change the results of the meta-analysis.

This meta-analysis still had some limitations and the results should be evaluated with caution. First, this meta-analysis is a type of secondary and retrospective study, it was limited by the quality of primary studies, and our meta-analysis was so, too. Second, we could not perform the analysis of gene-gene and gene-environment interactions.

In conclusion, this present study investigated the relationship between MMP2-735 C/T polymorphism and the susceptibility to cancer. We found that MMP2-735 C/T polymorphism may contribute to an increase in susceptibility to cancer in the Caucasian population. Further a lager study considering gene-gene and gene-environment interactions is needed to provide more evidence supporting the association of MMP2-735 C/T polymorphism with cancer risk.

Acknowledgements

This study was supported by the R & D program of MKE/KEIT (10040393, development and commercialization of molecular diagnostic technologies for lung cancer through clinical validation).

Disclosure of conflict of interest

None.

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