Functional haplotypes in the promoter of matrix metalloproteinase-2 and lung cancer susceptibility
Yifeng Zhou 1,
,
Chunyuan Yu 1,
,
Xiaoping Miao 1,
Yonggang Wang 2,
Wen Tan 1,
Tong Sun 1,
Xuemei Zhang 1,
Ping Xiong 1, 3 and
Dongxin Lin 1, *
1 Departments of Etiology and Carcinogenesis and 2 Department of Thoracic Surgery, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
3 Current address: Department of Epidemiology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
* To whom correspondence should be addressed. Tel: +86 10 87788491; Fax: 86 10 67722460; Email: dlin{at}public.bta.net.cn
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Abstract
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Matrix metalloproteinase-2 (MMP-2) plays important roles in cancer initiation and progression. Our previous studies revealed that the 1306C
T and 735C
T polymorphisms in MMP2 promoter significantly influence transcriptional activity and their genotypes and haplotypes are associated with susceptibility to several cancers. This casecontrol study examined the contribution of these two polymorphisms to the risk of developing lung cancer. MMP2 genotypes and haplotypes were determined in 770 cases and 777 controls and the associations with risk of lung cancer were estimated by logistic regression. We observed a 2-fold [odds ratio (OR), 2.12; 95% confidence interval (CI), 1.642.72] or 1.6-fold (OR, 1.57; 95% CI, 1.271.95) excess risk of developing lung cancer for the 1306CC or 735CC genotype carriers compared with non-carriers, respectively. A greater risk of lung cancer was associated with the C1306C735 haplotype (OR, 5.01; 95% CI, 2.579.78) compared with the T1306T735 haplotype, suggesting a synergic effect of these two polymorphisms. Furthermore, a greater than additive joint effect of the polymorphisms and smoking increased an even higher risk of lung cancer. The OR for smokers with the C1306C735 haplotype was 6.24 (95% CI, 4.518.64), which was significantly higher than that (OR, 4.10; 95% CI, 2.895.81) of smokers with the T1306 or T735-containing haplotypes (P < 0.001). These results are consistent with our previous findings and further support the hypothesis that gain-of-function of MMP2 resulting from genetic polymorphisms plays an important role in human carcinogenesis.
Abbreviations: CI, confidence interval; MMP-2, matrix metalloproteinase-2; OR, odds ratio; SCC, squamous cell carcinoma; SNP, single nucleotide polymorphism.
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Introduction
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Matrix metalloproteinase-2 (MMP-2), among other MMPs, plays a central role in degrading or breaking down extracellular matrix, a physical barrier in restraining the expanding growth and migration of tumor cells (13). Increased expression of MMP-2 has been associated with cancer invasive and metastatic phenotypes (46). However, expanding studies have demonstrated that, in addition to destroying extracellular matrix to permit tumor cell invasion and metastasis, MMP-2 also plays important roles in several steps of cancer development (7,8). New specific matrix and non-matrix substrates for MMP-2 have been identified and the biological consequences of cleavage of these substrates indicates that MMP-2 is involved in cell proliferation, apoptosis, angiogenesis and immune surveillance (7). For instance, MMP-2 can cleave insulin-like growth factors (IGFs)-binding proteins and release IGFs (9), which are well known to have a strong effect on stimulating cell proliferation and inhibiting apoptosis. Overexpression of MMP-2 has also been detected in precancerous lesions and early stage of human cancer (10,11), suggesting that it may be an early event in carcinogenesis. Furthermore, it has been demonstrated that high levels of constitutive expression of MMP-2 is associated with a high susceptibility to tumor formation in genetically modified animal models (12,13).
Human MMP2 gene exhibits sequence variations and several functional single nucleotide polymorphisms (SNPs) in the MMP2 promoter have been described (1416). A C
T polymorphism located at nucleotide 1306 site disrupts an Sp1 regulatory element and the T allele thus, has a strikingly lower promoter activity compared with the C allele (14). We have recently shown that another C
T polymorphism located at nucleotide 735 also destroys an Sp1 binding element, with the T allele being associated with significantly diminished promoter activity (16). Interestingly, the 1306C
T and 735C
T polymorphisms are in a linkage disequilibrium and the T1306T735 haplotype displays an even lower promoter activity and mRNA expression compared with the haplotype consisting of only one T allele at the 1306 or 735 site, indicating an interactive effect of these two SNPs on MMP2 transcriptional function (16).
The association between the 1306C
T polymorphism and susceptibility to human cancers has been investigated in several studies. It has been shown that the 1306C allele is associated with an increased risk of common cancers, including lung, gastric cardia, breast, oral and colorectal cancers (1721). Recently, we have explored the relationship between the 735C
T polymorphism, alone or in combination with the 1306C
T polymorphism, and risk of esophageal squamous cell carcinoma (SCC). We observed an increased risk of the cancer associated not only with the 1306C allele but also with the 735C allele; furthermore, an even greater association was observed between elevated risk of developing esophageal SCC and C1306- and C735-allele containing haplotypes (16).
In view of the important role that MMP-2 plays in cancer initiation and development, a more comprehensive study is warranted to evaluate the effect of MMP2 promoter haplotypes as a genetic modifier in the etiology of lung cancer, whose rates of incidence and mortality have been increasing significantly and constantly in China and most other parts of the world. Here, we report a large contribution of MMP2 C1306- and C735-allele containing haplotypes, alone or in combination with smoking, to the risk of developing lung cancer in a casecontrol study.
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Materials and methods
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Study subjects
Characteristics of the study subjects have been described previously (17). All subjects were ethnic Han Chinese. Patients were consecutively recruited between January 1997 and November 2001, at the Cancer Hospital, Chinese Academy of Medical Sciences (Beijing). All patients with histopathologically confirmed lung cancer were enrolled, yielding a 93% response rate; they were from Beijing City and surrounding regions. Controls were cancer-free individuals randomly selected from a nutritional survey consisting of 2500 individuals, which was conducted in the same period as the cases were collected. The selection criteria included no individual history of cancer and frequency matched to cases on sex and age (± 5 years). Of the 781 cases and 852 controls who participated in the previous study (17), only 770 cases and 777 controls were successfully genotyped in this study because DNA samples of the rest of the subjects were no longer available. At recruitment, informed consent was obtained from each subject and each participant was then interviewed to obtain detailed information on demographic characteristics and lifetime history of tobacco use. This study was approved by the Institutional Review Board of the Chinese Academy of Medical Sciences Cancer Institute.
MMP2 genotyping
Genotypes at the 1306 and 735 site were determined by PCR-based denaturing high performance liquid chromatography and PCR-based restriction fragment length polymorphism methods as described previously (16,17). Genotyping was performed with blinding to case/control status; a 15% masked, random sample of cases and controls was tested twice by different persons; and the results were concordant for all masked duplicated sets.
Statistical analysis
The
2 test was used to compare the distributions of MMP2 genotypes and haplotypes between cases and controls. Smokers were categorized as light smokers and heavy smokers by the approximate 50th percentile pack year value among controls, i.e. <26 or
26 pack years [(cigarettes per day/20) x (years smoked)]. HardyWeinberg equilibrium was tested by a goodness-of-fit
2 test. Linkage disequilibrium coefficient and haplotype frequencies were estimated using EH (EH-plus) and PHASE software, respectively (22,23). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated by unconditional logistic regression as a measure of association with risk of the development of lung cancer. The ORs were adjusted for age, sex and smoking status or pack years, where it was appropriate. A P-value of <0.05 was used as the criterion of statistical significance, and all statistical tests were two-sided. We tested the null hypotheses of additive and multiplicative gene smoking interaction and evaluated departures from additive and multiplicative interaction models (24) by including main effect variables and their product terms in the logistic regression model. A more than additive interaction was indicated when OR11 > OR10 + OR01 1, where OR11 = OR when both factors are present, OR10 = OR when only factor 1 is present, and OR01 = OR when only factor 2 is present. A more than multiplicative interaction was suggested when OR11 > OR10 x OR01. All statistical analyses were performed with computer programs from Statistical Analysis System (version 6.12; SAS Institute, Cary, NC).
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Results
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The relevant characteristics of study subjects are shown in Table I. There were no statistically significant differences between the cases and controls in terms of age and sex distributions (P = 0.170 and 0.613, respectively). However, as expected, more smokers were presented among cases compared with controls (65.2% versus 47.4%; P < 0.001). Furthermore, the cases had higher values of pack years smoked than the controls; 66.3% of smokers among the cases smoked an equivalent of
26 pack years, whereas this value was only 50.0% among the controls (P < 0.001). Among the cases, 318 (41.3%) were classified as SCC, 210 (27.3%) as adenocarcinoma (AC) and 242 (31.4%) as other types, including undifferentiated cancer (n = 93), bronchioalveolar carcinoma (n = 85) and mixed cell carcinoma (n = 64).
Genotyping data are presented in Table II. The frequencies of three MMP2 1306 or 735 genotypes among controls were not different from those expected from the HardyWeinberg equilibrium (P = 0.842 and 0.374). However, the genotype frequencies at both sites were significantly different between cases and controls (both P < 0.001), with the 1306CC and 735CC genotypes being overrepresented in cases. Multivariate analysis showed that the 1306CC genotype carriers had a 2-fold elevated risk for developing lung cancer (adjusted OR, 2.12; 95% CI, 1.642.72) compared with the non-carriers. Similarly, the 735CC genotype carriers was also at an increased risk of developing the cancer, compared with the TT or CT genotype carriers (adjusted OR, 1.57; 95% CI, 1.271.95). Moreover, the increased risk associated with the 735CC or 735CC genotype was consistently observed among different subtypes of lung cancer (Table II).
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Table II. Genotype and allele frequencies of MMP2 in cases and controls and their association with risk of lung cancer
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Linkage disequilibrium analysis showed that the 1306C
T and 735C
T polymorphisms were in a linkage disequilibrium (P < 0.001). The
2 test of statistical significance for a two-locus disequilibrium gave a test statistic value of 10.2 (D' = 0.53) for the cases, 11.0 (D' = 0.33) for the controls and 14.4 (D' = 0.33) for all subjects. MMP2 haplotypes in cases and controls were than constructed by using the PHASE software and the results are presented in Table III. The distribution of haplotype frequencies differed significantly between the cases and controls (
2 = 55.6, P < 0.0001, df = 3), with the T1306- or T735-containing haplotypes being more prevalent among controls than among cases. Compared with the T1306T735 haplotype, each of the other haplotype containing at least one 1306C or 735C allele was associated with an increased risk of lung cancer; the adjusted ORs for the T1306C735, C1306T735 and C1306C735 haplotypes were 3.01 (95% CI, 1.476.18), 3.81 (95% CI, 1.897.65) and 5.01 (95% CI, 2.579.78), respectively (trend test, P < 0.001).
The risk of lung cancer related to MMP2 genotypes and haplotypes were further examined with stratification by smoking status and pack year values (Tables IV and V). It was found that among non-smokers, the adjusted OR of lung cancer for subjects carrying the 1306CC or 735CC genotype was 2.09 (95% CI, 1.433.06) or 1.82 (95% CI, 1.312.52). However, among smokers, subjects carrying the CC genotype at 1306 or 735 site had an OR of 6.74 (95% CI, 4.1710.88) or 6.43 (95% CI, 4.149.99), respectively, which was significantly higher than that for those carrying at least one T allele at each site (OR, 3.86; 95% CI, 2.156.94 or OR, 4.09; 95% CI, 2.606.42) (P < 0.01, test for homogeneity). Since the OR for the presence of both smoking and the 1306CC or 735CC genotype was greater than the sum minus 1 of OR for smoking and OR for the corresponding genotype, these data suggested more than additive joint effects between these two genotypes and smoking (25). Moreover, these additive joint effects showed a smoking doseresponse manner, with the ORs for both 1306CC and 735CC genotypes being significantly higher among smokers who consumed an equivalent of
26 pack years compared with smokers who consumed an equivalent of <26 pack years (OR 9.01 versus OR 4.81, and OR 8.21 versus OR 4.14; both P < 0.001). A similar gene smoking interaction in the context of MMP2 haplotypes was also observed (Table V), with the OR being the highest for smokers who carried the C1306C732 haplotype and consumed an equivalent of
26 pack years (OR, 8.04; 95% CI, 5.5711.60).
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Discussion
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We have previously reported a significant association between the MMP2 1306CC genotype and increased risk of developing lung cancer (17). Recently, we have also identified a novel polymorphic site (735C
T) as an Sp1 binding site and found that the 735CC genotype was associated with an increased MMP-2 expression and increased risk of the occurrence and metastasis of esophageal cancer. Furthermore, the 735CC and 1306CC genotypes were in a linkage disequilibrium and functioned interactively in the context of haplotype (16). In the present study, we extended the findings to lung cancer, showing that not only the 1306CC genotype but also the 735CC genotype was a susceptibility factor and these two genotypes had a strong interaction within a haplotype to influence the risk of cancer; the C1306C732 haplotype was associated with a 5-fold increased risk of developing lung cancer compared with the T1306- or T732-containing haplotypes. Moreover, we observed a more than additive joint effect between the risk genotypes or haplotypes and smoking, which was associated with even greater risk of lung cancer. These extended findings further support our notion that gain-of-function of MMP2 resulting from genetic polymorphisms confers an individual susceptibility to certain common cancers (1619).
Overexpression of MMP-2 has been demonstrated to be an early event in the development of many types of human cancers, including lung cancer (10,11,26,27). Furthermore, this proteinase in lung tumors is produced not only by cancer cells but also by normal stromal cells and endothelial cells (2830), suggesting that the overexpression of MMP-2 is probably owing to transcriptional changes but not gene amplification or activating mutation. Indeed, we and others have demonstrated that the 1306 and 735 genotypes and haplotypes in the MMP2 promoter are associated with significantly different transcriptional activity of the gene (14,16). Although the differences in allele transcription resulting from polymorphisms in the MMP2 promoters are subtle compared with the overexpression that arises from the amplification of oncogenes, the increased level of MMP-2 over a lifetime might foster an increased susceptibility to tumorigenesis. Several studies with genetically modified animals are consistent with this notion. It was found that when induced by carcinogenic stimulus, wild-type mice having the Mmp2 or Mmp9 gene developed more tumors than mice that lack these genes (31). Cancer cells injected through the vein were found to be more capable of colonizing the lungs of wild-type mice than the lungs of Mmp2-knockout mice (12). Conversely, transgenic mice that overexpress membrane type MMP-1, a known activator of pro-MMP-2, were at an increased susceptibility to mammary tumor formation and metastasis (32). These experimental findings strongly support our observation that germline polymorphisms in the MMP2 promoter that cause high expression of MMP-2 over a lifetime may constitute an increased susceptibility to lung cancer.
Functional polymorphisms in some other MMP genes have also been linked to varying susceptibility to certain human cancers. It has been shown that a single guanine insertion polymorphism in the promoter region of MMP1 (2G allele), which creates an Est binding site and enhances transcriptional activity, has been associated with an increased risk for developing cancer of the lung, ovary, colo-rectum and endometrium compared with the 1G allele (3336). A single adenosine deletion polymorphism in the MMP3 promoter (5A allele) has been associated with a higher risk for breast cancer and esophageal cancer, compared with the 5A allele which has reduced transcriptional activity (37,38). These findings are parallel to our results reported here showing that genetic polymorphisms, which enhance MMP2 transcriptional activity, are associated with an increased susceptibility to lung cancer.
A joint effect between the MMP2 promoter polymorphisms and tobacco smoking was evident in the present study. We found that the 1306CC and 735CC genotypes or the C1306C732 haplotype were significantly associated with lung cancer risk in non-smokers; however, the risk was markedly elevated in smokers, particularly heavy smokers, suggesting an additive gene smoking interaction. Tobacco smoking is an established etiological factor for lung cancer; therefore, this gene smoking interaction is biologically plausible. A higher risk of lung cancer among smokers who carried the susceptible genotypes or haplotypes may be attributed to many transformed or preinvasive lung cells caused by tobacco carcinogens, which in turn increases the possibility that one of these cells will become an invasive tumor under the condition of higher lifetime expression of MMP-2. In addition, because MMPs expression can be induced by smoking (39,40), another hypothesis is that in addition to higher constitutive expression owing to gain of two Sp1 promoter sites, the inducibility of the C1306C732 haplotype of MMP2 by smoking may also be higher than that of the T1306T732 haplotype, which lacks two Sp1 sites. Given these conditions, it would be expected that subjects who smoked and carried the 1306CC and 735CC genotypes or the C1306C732 haplotype were more susceptible to developing lung cancer. Plans have been made to examine the mechanism(s) by which these MMP2 promoter SNPs modify the development of lung cancer.
In summary, this study provides further evidence that the functional genotype and haplotype in the MMP2 promoter are genetic susceptibility factors for lung carcinogenesis. These extended results are consistent with our previous findings in the studies of esophageal cancer, gastric cardia cancer and breast cancer, and further support the hypothesis that gain-of-function of MMP2 resulting from genetic polymorphisms plays an important role in human carcinogenesis.
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Notes
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The first two authors contributed equally to this work. 
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Acknowledgments
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This work was supported by grants 2002BA711A06 from National 863 High Technology Project and grant 2004CB518701 from State Key Basic Research Program.
Conflict of Interest Statement: None declared.
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Received November 30, 2004;
revised January 24, 2005;
accepted February 16, 2005.