Association of a haplotype of matrix metalloproteinase (MMP)-1 and MMP-3 polymorphisms with renal cell carcinoma
Hiroshi Hirata1,*,
Naoko Okayama2,*,
Katsusuke Naito1,3,
Ryo Inoue1,
Satoru Yoshihiro1,
Hideyasu Matsuyama1,
Yutaka Suehiro2,
Yuichiro Hamanaka2 and
Yuji Hinoda2
1 Department of Urology, Yamaguchi University School of Medicine, Yamaguchi, Japan and 2 Department of Clinical Laboratory Science, Yamaguchi University School of Medicine, Yamaguchi, Japan
3 To whom correspondence should be addressed Email: katsunai{at}po.cc.yamaguchi-u.ac.jp
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Abstract
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It has been shown that the matrix metalloproteinase (MMP)-1 promoter polymorphism 1G/2G is associated with an increased risk of developing various cancers including renal cell carcinoma (RCC), and is in linkage disequilibrium (LD) with the MMP-3 promoter polymorphism 5A/6A. These two genes are localized in 11q22 adjacent to each other. However, the relationship between the MMP-3 5A/6A polymorphism and susceptibility to cancer remains ambiguous. In this study, we genotyped eight polymorphisms in the region containing the MMP-1 and MMP-3 genes in 177 healthy subjects, and explored the relationships between RCC and these polymorphisms or haplotypes in 156 RCC cases and 230 age- and gender-matched controls. All the subjects studied were of Japanese descent. There were three polymorphisms that showed stronger LD with the MMP-1 1G/2G promoter variant than with the MMP-3 5A/6A promoter variant. One of these three polymorphisms was present in exon 2 of the MMP-3 gene and caused an amino acid change, Glu45Lys (G/A). When the genotype distribution of Glu45Lys was compared between RCC patients and controls, the frequency of the G/G genotype was significantly higher in the patients [age- and gender-adjusted odds ratio (OR) = 1.81, 95% confidence interval (CI) = 1.202.74]. A significant increase in the frequency of the 2G/2G genotype of the MMP-1 1G/2G polymorphism was also observed in the patients (age- and gender-adjusted OR = 1.86, CI = 1.232.82), whereas there was no significant difference for the MMP-3 5A/6A polymorphism. As expected based on these genotype-level results, the frequency of the 2G-G haplotype of MMP-1 1G/2G and MMP-3 Glu45Lys (G/A) polymorphisms was significantly higher in the patients than in the controls (crude OR = 1.95, CI = 1.312.91). These findings suggest that this haplotype of MMP-1 and MMP-3 variants may be associated with the risk of developing RCC.
Abbreviations: CI, confidence interval; LD, linkage disequilibrium; MMP, matrix metalloproteinase; OR, odds ratio; RCC, renal cell carcinoma; SNP, single nucleotide polymorphism
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Introduction
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Matrix metalloproteinase (MMP)-1 and MMP-3 are members of a family of extracellular matrix-degrading enzymes and have been implicated in tumor angiogenesis, invasion and metastasis (1,2). The MMP-1 1G/2G polymorphism, resulting from the insertion/deletion of a guanosine at nucleotide position 1607 (3), has been reported to be associated with a variety of malignancies, including ovarian cancer (4), lung cancer (5), colorectal cancer (6, 7), renal cell carcinoma (RCC) (8) and cervical cancer (9). Accumulating evidence suggests that this polymorphism is of functional importance. Rutter et al. reported that the 2G allele binds substantially more recombinant Ets-1, a transcription factor encoding a proto-oncogene, and has a significantly higher transcriptional activity than the 1G allele in normal fibroblasts and melanoma cells (3). More recently, it was shown that this polymorphism, together with an adjacent AP-1 (activation protein-1) binding site, significantly affects the induction of MMP-1 by hydrogen peroxide produced by manganese-superoxide dismutase (Sod2) (10), and that MMP-1 production is higher in human foreskin fibroblasts from 2G homozygotes than in those from 1G homozygotes when stimulated with epidermal growth factor or interleukin-1 (11). MMP-1 has also been implicated in carcinogenesis based on the finding that transgenic mice constitutively expressing MMP-1 within the skin epidermis had an increased susceptibility to tumorigenesis (12). Thus, MMP-1 can be regarded as a candidate susceptibility gene for cancer.
The MMP-3 gene is located adjacent to the telomere side of the MMP-1 gene on 11q22 and has a 5A/6A promoter polymorphism at 1171 due to the insertion/deletion of adenosine (13). The 5A allele had stronger promoter activity than the 6A allele in an in vitro study, and DNAprotein interaction assays showed that a nuclear protein bound more strongly to the 6A sequence than to the 5A sequence, suggesting that it may be a transcriptional repressor (13). The development of mammary tumors in MMP-3 transgenic mice suggested that it could be involved in carcinogenesis (14,15). However, few studies have investigated the possible association between the MMP-3 5A/6A polymorphism and susceptibility to cancer. Its association with breast cancer is controversial (16,17), and a negative finding was reported for ovarian cancer (18). We demonstrated previously that the MMP-1 1G/2G polymorphism is in linkage disequilibrium (LD) with the MMP-3 5A/6A polymorphism (7), and that both showed a significant association with colorectal cancer, although the association was weaker for MMP-3 5A/6A than for MMP-1 1G/2G (7). We also revealed that MMP-1 1G/2G could be associated with RCC (8), but there have been no reports on the relationship between MMP-3 5A/6A and RCC.
In this study, we genotyped additional polymorphisms in the MMP-1 and MMP-3 gene region, and attempted to find new polymorphisms that were in LD with MMP-1 1G/2G. Furthermore, a case-control study of RCC was conducted to investigate its putative association with the new polymorphisms and resultant haplotypes.
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Materials and methods
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Study population
The patients with conventional RCC and healthy controls evaluated in this study were recruited from the Yamaguchi University Hospital between 1999 and 2003. The diagnosis of conventional RCC was based on the histopathological findings. RCC was classified according to the WHO criteria and staged according to the tumor-node-metastasis classification. Healthy controls consisted of medical staff and outpatients who had no apparent abnormal findings upon medical examination. All patients and healthy controls were native Japanese and resided in Yamaguchi prefecture or adjacent prefectures. Written informed consent, which was approved by the institutional ethics committee of Yamaguchi University School of Medicine, was obtained from each subject. Peripheral blood or tissue samples were obtained from the patients and controls after the written informed consent was obtained. The participation rate was 100 and 98% for the patients and controls, respectively.
For the LD analysis of eight polymorphisms in the MMP-1 and MMP-3 gene region, peripheral blood was obtained from 177 randomly selected healthy volunteers. For the case-control study of RCC, peripheral blood or non-cancerous kidney tissue was obtained from 156 patients (110 males and 46 females) with conventional RCC, and 230 age- and gender-matched healthy control individuals.
DNA samples
Genomic DNA was extracted from the peripheral blood of 104 patients and 326 healthy individuals, and from fresh-frozen non-cancerous kidney tissue of 52 patients. The latter was snap-frozen at the time of surgery and stored at 80°C until use. DNAzol (Molecular Research Center, Cincinnati, OH) and GenTLE (TAKARA, Kyoto, Japan) were used to extract DNA from the normal tissue and peripheral blood, respectively, according to the manufacturers' protocols. The success rate of the DNA preparation was 100 and >99% in the patients and controls, respectively. There were no DNA samples that could not be subjected to genotyping.
Genotyping
Genotyping was performed using a tetra-primer amplification refractory mutation systempolymerase chain reaction (ARMSPCR) or a PCRrestriction fragment length polymorphism (RFLP) method as described previously (7,19).
Each PCR reaction was carried out in a total volume of 25 µl consisting of 0.5 µl of a 10 µM solution of each primer, 2.5 µl of 10x reaction buffer (100 mM TrisHCl pH 8.3 at 25°C, 500 mM KCl, 15 mM MgCl2), 4 µl of a 1.25 mM solution of 4 dNTPs, 1 µl of AmpliTaq DNA polymerase (Perkin Elmer, Branchburg, NJ, USA), 1 µl of genomic DNA (80 ng/µl) and 14.5 or 15.5 µl H2O using a Robocycler (Gene Amp PCR System 9600, Perkin Elmer) under the conditions of an initial denaturation for 2 min at 95°C followed by 30 cycles of 30 s at 95°C, 30 s at 51°C and 30 s at 72°C. The PCR products were separated by electrophoresis in a 2.0% agarose gel, and subsequently stained with ethidium bromide. For RFLP analysis, the PCR products were digested with restriction enzymes before electrophoresis.
To confirm the genotype ascribed by PCRRFLP, the PCR products were subjected to direct sequencing. Ten microliters of PCR products was incubated with 4 µl of ExoSAP-IT (Amersham Bioscience, Tokyo, Japan) for 15 min at 37°C and then for 15 min at 80°C. Sequencing reactions were subsequently carried out using a BigDye Terminator Cycle Sequencing FS Ready Reaction Kit (Applied Biosystems, Tokyo, Japan). After purification with a Centri-Sep spin column (Applied Biosystems), the reaction products were analyzed using an ABI PRISM 377 DNA sequencer (Applied Biosystems).
The MMP polymorphisms tested and the primers used in this study are shown in Figure 1 and Table I, respectively. PCRRFLP was used to genotype MMP-1 1G/2G, MMP-3 5A/6A, rs491152, rs470206, rs1144396, rs650108 and Glu487Lys of aldehyde dehydrogenase 2 (ALDH2), and the data were validated by direct sequencing. ALDH2 genotyping was performed according to Harada and Zhang (20). Rs2071231 and rs679620 were genotyped by tetra-primer ARMSPCR with validation by PCRRFLP. These validation assays were performed on all the data for rs491152, rs470206, rs1144396, rs650108, rs2071231, rs679620 and Glu487Lys of ALDH2 in the 177 control samples used for the LD analysis. For the MMP-1 1G/2G and MMP-3 5A/6A polymorphisms, the validation assays were unnecessary since the assay conditions for these single nucleotide polymorphisms (SNPs) were established previously (7,8). There were no DNA samples showing discrepant results between the two methods.

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Fig. 1. Polymorphisms tested in the MMP-1 and MMP-3 gene region. The variants, except for the MMP-1 1G/2G and MMP-3 5A/6A, are indicated by the NCBI SNP Cluster ID.
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Statistical analysis
The genotypes concerning the MMP-1 1G/2G, MMP-3 5A/6A and MMP-3 A/G polymorphisms did not show departure from the HardyWeinberg equilibrium when the control samples for the LD analysis (n = 177) and those for the case-control study (n = 230) were separately examined or when all the samples were combined before analysis (n = 326) (P > 0.05). Two-tailed Student's t-tests were used to compare the distributions of age and gender between patients and control subjects. The strength of associations between RCC patients and MMP polymorphisms were measured as odds ratios (ORs). The ORs were obtained with unconditional logistic regression. Crude ORs and those adjusted for age and gender were calculated. The statistical analyses were performed using StatView (version 5; SAS Institute Inc., NC). HardyWeinberg equilibrium, LD and haplotype frequency were evaluated using SNPAlyze version 2.2 (DYNACOM, Tokyo, Japan). Power was calculated using the PS program, version 2.1.30, created by W.D. Dupont and W.D. Plummer Jr. Power calculations for the MMP-1 1G/2G polymorphism indicated that the analyses had the power to detect an OR of 1.8 at the 5% significance level for
80% or more likelihood for RCC development. The required number of RCC patients, based on 80% power and 5% type I error, was 147 when the ratio of control subjects to patients was 2.
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Results
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In this study, DNA samples from 156 RCC patients and 326 healthy controls were subjected to genotyping for the MMP-1 and MMP-3 polymorphisms. For the case-control study, 230 samples from age- and gender-matched healthy volunteers were selected and compared with RCC patients, while 177 samples from randomly selected healthy volunteers were used for the LD analysis. Eighty-one of the latter 177 samples were also used for the case-control study. To adjust for age, the number of subjects in each decade of life from their 20s to 90s was roughly matched between cases and controls. The mean ages in the patient and control groups were 63.3 (range 3284) and 64.9 years (range 3499), respectively. Data regarding the history of family members, smoking and alcohol intake were obtained from RCC patients via interviews by doctors or nurses, and reviewed by the researchers. BMI was measured on admission. For the healthy controls, only age and gender were recorded as personal data. The demographic information for the cases and controls are shown in Table II. Significant differences were seen in the distributions of age and gender when the 177 randomly selected healthy volunteers were compared with the RCC patients (P < 0.01). Although the data for smoking among the controls were not available, the percentage of smokers among the patients tested did not seem to differ much from that among the entire Japanese population. The percentages of smokers among men and women in Japan in 2002 were 49 and 14%, respectively (21), while those for the patients in this study were 50.9% for men and 6.3% for women.
To evaluate whether the patient and two control groups used in this study were representative of the entire population in Japan, an irrelevant polymorphism, Glu487Lys of ALDH2 (20), was genotyped in all samples, and the data were compared with those of previous reports on Japanese subjects (22,23). As shown in Table III, there were no significant differences in the genotype distributions among our three groups and two other groups.
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Table III. Genotype distribution of Glu487Lys of ALDH2 in all the samples used in this study and in previous reports on Japanese
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In addition to the previously reported MMP-1 1G/2G and MMP-3 5A/6A promoter polymorphisms, six further polymorphisms in the MMP-1 and MMP-3 gene region were genotyped in the 177 healthy volunteers (Table IV). The LD among these was then calculated (Table V). As described previously (7), MMP-1 1G/2G was in LD with MMP-3 5A/6A (Table V). However, three of the polymorphisms, rs1144396, rs65108 and rs679620, were in stronger LD with MMP-1 1G/2G than with MMP-3 5A/6A (Table V). Among these three variants, rs679620 was present in exon 2 of the MMP-3 gene and resulted in a non-synonymous amino acid substitution, Glu45Lys (G/A).
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Table IV. Genotype frequencies of eight polymorphisms over the MMP-1 and MMP-3 gene region in 177 healthy individuals
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The genotype distribution of the MMP-3 Glu45Lys (G/A) polymorphism was compared between RCC patients and age- and gender-adjusted controls (n = 230) (Table VI). The frequency of the G/G genotype was significantly higher in the patients than in the controls [age- and gender-adjusted OR = 1.81, 95% confidence interval (CI) = 1.202.74]. A significant increase in the 2G/2G genotype of the MMP-1 1G/2G polymorphism was also observed in the patients (age- and gender-adjusted OR = 1.86, CI = 1.232.82), consistent with our previous data (8). In contrast, the 6A/6A genotype of the MMP-3 5A/6A polymorphism showed no significant difference between the patients and the controls (Table VI).
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Table VI. Comparison of genotype frequencies of MMP-3 rs679620, MMP-1 1G/2G and MMP-3 5A/6A between RCC patients and controls
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The distribution of haplotypes of the MMP-1 1G/2G and MMP-3 Glu45Lys polymorphisms were compared between RCC patients and controls. As shown in Table VII, a significant increase in the most frequent haplotype, 2G-G, was seen in the patients compared with the controls (crude OR = 1.95, CI = 1.312.91).
The relationships between various clinicopathological or epidemiological factors and the MMP-1 1G/2G and MMP-3 Glu45Lys polymorphisms were evaluated for the RCC patients, but none of the factors showed any significant association (data not shown).
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Discussion
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As shown in Table II, two control groups were used in this study. One consisted of 177 randomly selected healthy volunteers who were subjected to LD analysis, and the other consisted of 230 age- and gender-adjusted healthy volunteers for the case-control study. Although the distributions of age and gender in the control group for the LD analysis were apparently different from the patient group and the other control group (Table II), there were no significant differences in the genotype distribution of an irrelevant polymorphism, Glu487Lys of ALDH2, among these three groups. Moreover, our data were very similar to those of two other reports on Japanese subjects. These results suggested that none of the three groups deviated genetically from the entire population in Japan.
Regarding the patient samples, 52 were obtained from fresh-frozen non-cancerous kidney tissues while 104 were from peripheral blood. It is generally considered that there are no differences between peripheral blood and tissues as sources of DNA for genotyping, and hence the only issue when using tissue appears to be possible contamination by cancer cells that may have acquired mutations. We genotyped previously the MMP-1 promoter SNP in 21 RCC tissues to detect the LOH of 11q22 by direct sequencing, but neither LOH nor point mutations were found (8). Furthermore, a growth pattern of diffuse invasion is rarely seen in RCC, and hence the possibility of contamination of non-cancerous tissues by cancer cells is thought to be rare.
Our previous findings that the MMP-1 2G allele was in LD with the MMP-3 6A allele and that the 2G-6A haplotype was significantly associated with colorectal cancer seemed to be contradictory (7), since it had been shown in vitro that the 2G allele up-regulates the transcription of the MMP-1 gene whereas the 6A allele down-regulates that of the MMP-3 gene (3,14). In this study, however, we demonstrated polymorphisms that showed much stronger LD with MMP-1 1G/2G than with MMP-3 5A/6A. These findings may explain why the association of MMP-3 5A/6A with cancer was less unambiguous in previous case-control studies (7,1618). Our present data also indicated that MMP-3 5A/6A was not associated with RCC (Table VI).
It is interesting that one of the three newly identified MMP-3 polymorphisms in LD with MMP-1 1G/2G causes a non-synonymous amino acid substitution of Glu to Lys (G to A). The functional significance of this remains unknown at the present time, although it does not seem to be a marker for MMP-1 1G/2G. This variant is present in the propeptide region of MMP-3, which is proteolytically removed to form the mature peptide. Enzymatic activation of pro-MMP-3 coincides with cleavage of the N-terminal 82-aa peptide region from the catalytic domain, which may contain many sites cleaved by proteases (24,25). Thus, the Glu/Lys amino acid change may affect the efficiency of active MMP-3 production.
Although it remains unknown whether MMP-3 influences the carcinogenesis of RCC, a transgenic mouse study suggested the involvement of MMP-3 in mammary tumor development (14). This role of MMP-3 could be complicated due to its diverse functions, including degradation of numerous extracellular matrix components, activation of gelatinase B, collagenases and some protease inhibitors, release of a number of cell surface molecules such as E-cadherin and induction of apoptosis (15). Among these, activation of collagenase-1 (MMP-1) may be an important mechanism for RCC development, since our data demonstrated an association between the 2G-G haplotype of MMP-1 1G/2G and MMP-3 A/G (Lys/Glu) and RCC. If the G allele of MMP-3 A/G is involved in its activation, it may enhance the activation of MMP-1, while the expression level of MMP-1 could be increased due to the 2G allele. The importance of MMP-1 in carcinogenesis has also been suggested in a mouse model, in which mice expressing an MMP-1 transgene in the epidermis exhibited hyperproliferation such as acanthosis, hyperkeratosis and basal cell proliferation, probably due to disruption of the epidermal architecture (12). Hyperproliferation is one of the stages observed during the progression of neoplasia (26). In these mice, tumor incidence was markedly accelerated when they were subjected to a two-stage carcinogenesis protocol with DMBA and TPA (12).
According to the NCBI database, there are three and one non-synonymous SNPs in the MMP-1 and MMP-3 genes, respectively. Since the frequency of minor alleles was very low and not in LD with the 1G/2G variant for any of these MMP-1 SNPs (data not shown), MMP-3 Glu45Lys may be the only non-synonymous SNP that is in LD with MMP-1 1G/2G in the region of the MMP-1 and MMP-3 genes, suggesting the importance of this SNP as a susceptibility locus. Further studies will be required to determine the size of the haplotype block and to search for other functional SNPs within it.
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Notes
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* These authors contributed equally to this work. 
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Acknowledgments
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The authors thank Ms K.Kurafuji for her technical assistance.
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Received January 19, 2004;
revised July 13, 2004;
accepted August 2, 2004.