MMP7 −181G Allele Is a Low-Penetrant Risk Factor for Cancer Development in East Asians

Abstract

Matrix metalloproteinase-7 (MMP-7) is a small secreted proteolytic enzyme with broad substrate specificity. Its expression is associated with tumor invasion, metastasis, and survival for a number of cancers. However, data from published studies with individually low statistical power are conflicting. Here, we performed a meta-analysis of 14 publications (16 case–control studies) to better assess the purported relationship. Eligible studies were identified by searching the Pubmed database. Odds ratios (ORs) with 95% confidence intervals (CIs) were estimated to assess the association. Overall, we found that the −181 G allele increased cancer risk in East Asians (G-allele vs. A-allele, OR=1.35, 95% CI: 1.25–1.46, P _{heterogeneity}=0.01; GA vs. AA, OR=1.40, 95% CI: 1.16–1.69, P _{heterogeneity}=0.04; GG+GA vs. AA, OR=1.52, 95% CI: 1.30–1.78, P _{heterogeneity}=0.00). Similarly, in the stratified analysis by cancer type and source of control, significantly increased cancer risk was indicated. Our study showed evidence that MMP7 −181A/G polymorphism may increase cancer risk in the East Asian population. Future studies with larger sample size are warranted to further evaluate this association in greater detail.

Introduction

M atrix metalloproteinases (MMPs) are a family of zinc-dependent proteinases that are capable of cleaving all extracellular matrix (ECM) substrates and regulating various cell behaviors (Chakraborti et al., 2003), thereby contributing to physiological events (Malemud, 2006) (tissue remodeling in pregnancy, wound healing and angiogenesis) and pathological conditions (VanSaun and Matrisian, 2006) (cancer, heart failure, arthritis, and periodontitis). Now, growing evidence shows that MMPs play an important role in several steps of cancer development by regulating cancer cell growth, differentiation, apoptosis, angiogenesis, invasion, and metastasis by degrading the ECM and basement membrane barriers (Forget et al., 1999; Egeblad and Werb, 2002). MMP7 is an important member of the MMPs family that has broad substrate specificity against both ECM and non-ECM components (Wilson and Matrisian, 1999). Best known as a contributor to tumor invasion and metastasis, MMP7 is involved in early stages of tumorigenesis, including cellular transformation, cell survival, tumor growth, angiogenesis, and evasion of immune surveillance (Egeblad and Werb, 2002; Hojilla et al., 2003; Hulboy et al., 2004; Ii et al., 2006).

MMP7 (also known as matrilysin or punctuated metalloproteinase-1, PUMP-1), which is encoded on chromosome 11q21-22, degrades elastin, proteoglycans, fibronectin, and type IV collagen (Wilson and Matrisian, 1999). In a transient transfection study, the promoter activity of the MMP7 −181 (rs11568818) G allele is 2- to 3-fold higher than that of the A allele, which may induce elevation of MMP7 mRNA transcription and subsequently increase its protein levels (Jormsjö et al., 2001). The substitution of A by the G allele implies higher activity of the promoter region, thereby increasing the levels of MMP7, and this is a possible mechanism by which MMP7 −181A/G polymorphism is related to an increase in the development of cancer.

Numerous studies on the association of this polymorphism with cancer susceptibility have been carried out; however, the results remain inconclusive. A quantitative synthesis to accumulate data from different studies is needed to provide better evidence on the relationship. In this article, we performed a meta-analysis of 14 publications (Zhang et al., 2005; Kubben et al., 2006; Li et al., 2006; Lu et al., 2007; Vairaktaris et al., 2007; Woo et al., 2007; Qiu et al., 2008; Singh et al., 2008; Sugimoto et al., 2008; Fang et al., 2010; Malik et al., 2010; Srivastava et al., 2010; Yi et al., 2010; Wu et al., 2011) to estimate the effect of MMP7 −181A/G polymorphism on cancer risk.

Materials and Methods

Literature search and data extraction

We conducted searches on the PubMed database (www.ncbi.nlm.nih.gov/), last search updated on May 10 2011, with the keywords “MMP7” or “matrix metalloproteinase-7”, “polymorphism,” and “cancer” or “carcinoma”, without any restriction on language or publication year. We also screened references of the retrieved articles and review articles by hand. Two of the authors reviewed results of each of the database searches to make sure that published papers had not been missed.

Inclusion and exclusion criteria

Eligible studies had to meet the following criteria: (a) the study assessed the correlation between global cancer and MMP7 −181A/G polymorphism; (b) case–control studies; (c) control subjects matched with case patients for age and gender; (d) only full-text manuscripts were included; and (e) all the individuals were East Asians. Major exclusion criteria were (a) no control population; (b) no available genotype frequency; and (c) duplication of the previous publications.

Data extraction

Data were collected on the first author's last name, year of publication, country of origin, cancer type, number of cases and controls, study design, subjects of genotype in cases and controls, source of control, and Hardy–Weinberg equilibrium (HWE) of controls and G% in the control groups.

Statistic analysis

Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to measure the strength of the association between MMP7 −181A/G polymorphism and cancer risk based on the genotype frequencies in cases and controls. Subgroup analysis stratified by race was performed first. If one cancer type contained only one individual study, then it was combined into the “other cancers” subgroup. Source of control subgroup analysis was performed on two classifications: population-based and hospital-based.

The fixed-effects model and the random-effects model were used to calculate the pooled OR. The statistical significance of the summary OR was determined with the Z-test. Heterogeneity assumption was evaluated with a chi-square-based Q test among the studies. A p-value of>0.05 for the Q-test indicated a lack of heterogeneity among the studies. If the p-value for heterogeneity was<0.05 using Q-test, then the random-effects model (DerSimonian and Laird method) was adopted (DerSimonian and Laird, 1986); in contrast, the fixed-effects model (Mantel–Haenszel method) was chosen (Mantel and Haenszel, 1959). The OR and 95% CI value were calculated under different models. To better evaluate the extent of heterogeneity between studies, the I ² test was also used. As a guide, I ² values of<25% may be considered low, values of 25%–50% may be considered moderate, and values of>75% may be considered high (Higgins et al., 2003). For MMP7 −181A/G polymorphism, we investigated the association between genetic variants and cancer risk in the dominant genetic model (GG+GA vs. AA), heterozygote comparison (GA vs. AA), and allelic contrast (G-allele vs. A-allele). The funnel plot asymmetry was assessed with Egger's test. Publication bias was assessed with Egger's test, and p<0.05 was considered statistically significant (Egger et al., 1997). The departure of frequencies of MMP7 −181A/G polymorphism from expectation under HWE was assessed by χ ² test in controls by using the Pearson chi-square test, and p<0.05 was considered significant. All statistical tests for our meta-analysis were performed with Stata software (version 10.0; StataCorp LP, College Station, TX).

Results

Eligible studies

Overall, we identified 14 articles (16 case–control studies; 14 different first authors) to evaluate the association of MMP7 −181A/G polymorphism with cancer risk. One study (Lu et al., 2007) was excluded, because the same authors published several reports on the same patients and controls, and only the most complete study was selected. The analysis includes 16 studies with 3099 cases and 4280 controls concerning the MMP7 −181A/G polymorphism and cancer risk. Characteristics of studies of MMP7 −181A/G polymorphism are summarized in Table 1. Cases in most of the studies were histologically diagnosed, and controls were free from cancer.

Table 1.

Characteristics of Studies of MMP7 −181A/G Polymorphism and Cancer Risk Included in Our Meta-Analysis

						Case	Control
Author	Year	Country	Cancer type	Case/control	Design	GG/GA/AA	GG/GA/AA	P_HWE	G%
Wu et al.	2011	China	Cervical cancer	217/190	PB	20/84/113	5/84/101	0.010	0.247
Malik et al.	2010	India	Gastric cancer	108/195	HB	40/39/29	40/92/63	0.547	0.441
Yi et al.	2010	Taiwan	Endometrial cancer	118/229	PB	6/27/85	2/40/187	0.931	0.096
Srivastava et al.	2010	India	Bladder cancer	200/200	HB	52/84/64	30/97/73	0.810	0.396
Fang et al.	2010	China	Colorectal cancer	237/504	HB	0/19/218	0/30/474	0.491	0.029
Sugimoto et al.	2008	Japan	Gastric cancer	160/156	PB	0/27/133	1/14/141	0.987	0.051
Qiu et al.	2008	China	Hepatocellular cancer	425/475	PB	1/50/374	0/40/435	0.338	0.042
Singh et al.	2008	India	Cervical cancer	150/162	HB	44/69/37	31/82/49	0.750	0.444
Woo et al.	2007	Korea	Colorectal cancer	185/304	HB	0/22/163	0/39/265	0.232	0.064
Lu et al.	2007	China	Brain astrocytoma	221/366	HB	9/32/180	2/35/329	0.319	0.053
Vairaktaris et al.	2007	Germany	Oral cancer	159/120	PB	27/92/40	28/46/46	0.018	0.425
Li et al.	2006	China	Ovarian cancer	138/160	HB	0/24/114	0/9/151	0.714	0.028
Kubben et al.	2006	Netherlands	Gastric cancer	79/169	HB	8/37/34	17/106/46	0.000	0.414
Zhang et al.	2005	China	Esophageal cancer	258/350	HB	1/41/216	1/33/316	0.888	0.050
			Gastric cancer	201/350	HB	0/34/167	1/33/316	0.888	0.050
			Lung cancer	243/350	HB	3/40/200	1/33/316	0.888	0.050

HB, hospital-based; PB, population-based; P _HWE, Hardy–Weinberg equilibrium of control; G%, the G allele frequency in control group.

For the MMP7 −181A/G polymorphism in East Asians, there were three studies of gastric cancer, two of cervical cancer, two of colorectal cancer, and seven of other cancers. Hospital-based cases were used in 10 studies. Zhang et al. (2005) investigated three types of cancer in one publication. All the included studies used the polymerase chain reaction restriction fragment length polymorphism method to analysis genotypes. Except for three case–control studies (Kubben et al., 2006; Vairaktaris et al., 2007; Wu et al., 2011), all the data were consistent with the HWE.

Quantitative synthesis and test of heterogeneity

In the overall analysis, significantly increased association could be observed between cancer risk and the variant genotypes of MMP7 −181A/G polymorphism for East Asians, but not for Caucasians: in the allelic contrast (OR=1.35, 95% CI=1.25–1.46, P _{heterogeneity}=0.01, p<0.01, I ²=48.7), the heterozygote comparison (OR=1.40, 95% CI=1.16–1.69, P _{heterogeneity}=0.04, p<0.01, I ²=43.4), and the dominant models (OR=1.52, 95% CI=1.30–1.78, P _{heterogeneity}<0.01, p<0.01, I ²=65.7) (Table 2).

Table 2.

Stratified Analyses of the MMP7 −181A/G Polymorphism on Cancer Risk

			G-allele vs. A-allele	GA vs. AA	GG+GA vs. AA
Variables	n	Cases/controls	OR (95% CI) P_h/P/I²	OR (95% CI) P_h/P/I²	OR (95% CI) P_h/P/I²
Race
East Asian	14	2861/3991	1.35 (1.25–1.46)0.01/0.00/48.7	1.40 (1.16–1.69)0.04/0.00/43.4	1.26 (1.17–1.36)0.00/0.00/65.7
Caucasian	2	238/289	0.96 (0.83–1.12)0.07/0.63/68.8	1.04 (0.22–4.93)0.00/0.96/93.3	0.96 (0.26–3.50)0.00/0.95/91.4
East Asian
Cancer type
Gastric cancer	3	469/701	1.36 (1.16–1.59)0.32/0.00/12.0	1.53 (0.92–2.55)0.01/0.10/55.6	1.64 (1.19–2.27)0.02/0.00/74.5
Cervical cancer	2	367/352	1.17 (1.02–1.34) 0.89/0.02/0.0	0.99 (0.85–1.14) 0.49/0.85/0.0	1.05 (0.93–1.19) 0.65/0.39/0.0
Colorectal cancer	2	422/808	1.09 (0.75–1.59)0.33/0.64/0.0	1.09 (0.76–1.57)0.32/0.64/0.0	1.09 (0.76–1.57)0.32/0.64/0.0
Other cancers	7	1603/2130	1.76 (1.46–2.11)0.01/0.00/62.9	1.60 (1.26–2.04)0.01/0.00/67.8	1.73 (1.41–2.12)0.00/0.00/74.6
Source of control
Hospital-based	10	1941/2941	1.59 (1.35–1.87)0.01/0.00/58.4	1.44 (1.14–21.8)0.05/0.00/47.2	1.57 (1.29–1.91)0.00/0.00/71.6
Population-based	4	920/1050	1.35 (1.14–1.60)0.29/0.00/19.3	1.19 (1.00–1.42)0.06/0.05/59.6	1.25 (1.06–1.48)0.10/0.01/52.7

P _h, the value for heterogeneity in each subgroup; P, the statistical value; OR, odds ratio.

In the stratified analysis by cancer type in East Asians, a significant association was found between MMP7 –181A/G polymorphism and gastric, cervical, and other cancers (Gastric cancer: OR=1.36, 95% CI=1.16–1.59, P _{heterogeneity}=0.32, p<0.01, I ²=12.0 for G-allele vs. A-allele; OR=1.64, 95% CI=1.19–2.27, P _{heterogeneity}=0.02, p<0.01, I ²=74.5 for GG+GA vs. AA. Cervical cancer: OR=1.17, 95% CI=1.02–1.34, P _{heterogeneity}=0.89, p=0.02, I ²=0.0 for G allele vs. A allele. Other cancer: OR=1.76, 95% CI=1.46–2.11, P _{heterogeneity}=0.01, p<0.01, I ²=62.9 for G allele vs. A allele; OR=1.60, 95% CI=1.26–2.04, P _{heterogeneity}=0.01, p<0.01, I ²=67.8 for GA vs. AA; OR=1.73, 95% CI=1.41–2.12, P _{heterogeneity}<0.01, p<0.01, I ²=74.6 for GG+GA vs. AA). Similarly, in the subgroup of source of control, significantly increased association was found in hospital-based or population-based groups in several genetic models (Table 2).

Sensitivity analysis and publication bias

Sensitivity analysis was performed to assess the influence of each individual study on the pooled OR by sequential removal of individual studies. The results suggested that no individual study significantly affected the overall OR in a dominant manner. The Begg's funnel plot and Egger's test were performed to access the publication bias of literatures. The shape of the funnel plots seemed asymmetrical in allele comparison for MMP7 –181A/G polymorphism, thus suggesting the presence of publication bias. Then, Egger's test was used to provide statistical evidence of funnel plot symmetry. As expected, the results have not shown an obvious evidence of publication bias in overall and East Asian analysis (Table 3).

Table 3.

Publication Bias Tests (Begg's Funnel Plot for Publication Bias Test) for MMP7 −181A/G Polymorphism

Genetic type	Coefficient	Standard error	t	p-value	95% CI of intercept
Total
G-allele versus A-allele	2.083	1.347	1.55	0.144	(−0.807, 4.973)
GA versus AA	3.151	2.560	1.23	0.239	(−2.340, 8.642)
GG+GA versus AA	2.385	2.290	1.04	0.315	(−2.526, 7.297)
East Asian
G-allele versus A-allele	1.890	1.014	1.86	0.087	(−0.319, 4.098)
GA versus AA	4.022	1.960	2.05	0.063	(−0.248, 8.291)
GG+GA versus AA	3.461	1.615	2.14	0.053	(−0.059, 6.980)

Discussion

This analysis, based on 16 case–control studies with 3099 cases and 4280 controls, explored the association between MMP7 −181A/G polymorphism and cancer risk. The results showed that there was a significant association between MMP7 single nucleotide polymorphism (SNP) −181 and cancer risk in East Asians. Moreover, the variant genotypes were associated with significantly increased gastric, cervical, and other cancers. A similar trend was detected among both population-based and hospital-based studies. SNPs are the most abundant form of genetic variation in the human genome. By convention, a point mutation is referred to as a SNP when the frequency of the minor (rarer) allele exceeds 1% in at least one population (Matsumura et al., 2005). It is thought that SNPs contribute to inter-individual variability in susceptibility to common diseases such as cancer (Sugimoto et al., 2006). MMP7 is a protease with a broad substrate specificity. It is not only able to degrade elastin, proteoglycans, fibronectin, and type IV collagen, but also can cleave nonmatrix substrates from the cell surface, including VE-cadherin, pro-tumor necrosis factor α, insulin-like growth factor binding proteins, and Fas ligand. Overexpression of MMP7 has been shown to occur in wide types of cancers, such as tumors of esophagus, colorectum, and kidney. Further, MMP7 expression has been shown to be associated with metastasis, disease progression, and decreased survival among patients with esophageal, gastric, colorectal, and renal cancer (Tanioka et al., 2003; Kitoh et al., 2004; Miyata et al., 2006; Wang et al., 2006).

The main conclusion of our meta-analysis is that significantly increased associations were found between whole cancer and MMP7 −181A/G polymorphism in East Asians. Genes may play various roles in different cancers. For this reason, we divided the cancers into four different cancer groups, including gastric cancer, cervical cancer, colorectal cancer, and other cancers. In our study, MMP7 −181A/G allele represents a risk factor in gastric cancer and cervical cancer. Malik et al. (2011) reported that people with the MMP7 −181 GG genotype had a 2.13-fold increased risk of gastric cancer. Singh et al. (2008) reported that individuals with the −181 GG genotype or −181 G allele had a 1.94-fold or 1.37-fold higher risk of cervical cancer, respectively. Our data analysis supports these findings. Our study has several limitations. First of all, the number of published studies included in our meta-analysis was not sufficient for a comprehensive analysis. Since only studies that were indexed by the selected database were included for data analysis, some relevant published studies in other databases may be missed, which may have biased our results. Third, publication bias might have occurred, and our Egger's test results may have a substantial risk of being affected by such bias, although the funnel plots as well as Egger's linear regression tests indicated no remarkable publication biases in this meta-analysis. Fourth, lack of individual data from each study prevents more detailed analysis, such as joint effects of SNP-SNP, gene-environment factors, age, sex, and metastasis/differentiation status. Fifth, one group of authors studied three kinds of cancer using the same healthy people as the control group; however, we calculated the control number three times (Zhang et al., 2005).

In summary, this meta-analysis suggests that MMP7 −181A/G polymorphisms may increase risk for overall cancer or some types of cancers in East Asian populations, but not for Caucasians. We encourage future evaluations on the contribution of this polymorphism to cancer risk in large sample sizes, more comprehensive and well-designed association studies.

Footnotes

Disclosure Statement

No competing financial interests exist. The authors are fully responsible for all the content and editorial decisions and have not received any financial support or other form of remuneration related to the development of this article.

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