The functional SNP in the matrix metalloproteinase-3 promoter modifies susceptibility and lymphatic metastasis in esophageal squamous cell carcinoma but not in gastric cardiac adenocarcinoma
Jianhui Zhang2,
Xia Jin,
Shumei Fang,
Yan Li,
Rui Wang1,
Wei Guo,
Na Wang,
Yimin Wang,
Denggui Wen,
Lizhen Wei,
Gang Kuang and
Zhiming Dong
Hebei Cancer Institute and 1 The Fourth Affiliated Hospital, Hebei Medical University, Jiankanglu 12, Shijiazhuang 050011, Hebei Province, China
2 To whom correspondence should be addressed. Tel: +86 311 6093338; Fax: +86 311 6077634; Email: jianhuizh{at}hotmail.com
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Abstract
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The matrix metalloproteinases (MMPs), a family of proteolytic enzymes that degrade different components of the extracellular matrix, play important roles in tumor development and invasion. A single adenine insertion/deletion polymorphism (6A/5A) in the MMP3 promoter region causes transcriptional elevation. The aim of this study was to assess the effects of this single nucleotide polymorphism (SNP) on the development and clinical staging of esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA). The MMP3 SNP was genotyped by polymerase chain reaction-restriction fragment length polymorphism analysis in 417 cancer patients (234 ESCC and 183 GCA) and 350 controls in north China. The overall distribution of the MMP3 SNP in ESCC and GCA patients was not significantly different from that in healthy controls. However, smoking individuals with the 5A/5A or 5A/6A genotype were significantly more common in ESCC patients than in controls (37.5 versus 23.3%,
2 = 5.13, P = 0.02). Thus, smokers with at least one 5A allele had a significantly increased risk of ESCC, compared with 6A homozygotes (age and sex adjusted OR = 1.95, 95% CI = 1.083.53). The significant difference in the SNP distribution between ESCC patients, GCA patients and controls was not observed when stratified by family history of upper gastrointestinal cancer. In addition, the frequency of the 5A/5A + 5A/6A genotypes in ESCC patients with and without lymphatic metastasis was significantly different (45.8 versus 27.8%,
2 = 4.56, P = 0.03). Therefore, patients with at least one 5A allele were significantly more prone to lymphatic metastasis of ESCC. In contrast, no significant difference in the SNP distribution between patients with and without lymphatic metastasis was observed in GCA. The present study suggests that the MMP3 promoter SNP might be associated with a risk of development and lymphatic metastasis in ESCC but not in GCA.
Abbreviations: 95% CI, 95% confidence interval; ECM, extracellular matrix; ESCC, esophageal squamous cell carcinoma; GCA, gastric cardiac adenocarcinoma; MMPs, matrix metalloproteinases; OR, odds ratio; SNP, single nucleotide polymorphism; UGIC, upper gastrointestinal cancers
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Introduction
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Tumor development is a multistep process involving many complex molecular events. The initial steps of tumor invasion are detachment of transformed cells from their point of origin, traversal of the interstitial matrix and basement membrane and invasion of the lymphatic-vascular channels. The matrix metalloproteinases (MMPs), a family of highly conserved zinc-dependent proteolytic enzymes that degrade many different components of the extracellular matrix (ECM) and regulate various cell behaviors, play important roles in tumor development and metastasis (13). Expression of most MMPs is normally low in tissues and is induced when remodeling of the ECM is required. MMP expression in tumors is regulated primarily at the transcriptional level, but there is also evidence of modulation of mRNA stability in response to growth factors and cytokines secreted by tumor-infiltrating inflammatory cells as well as by tumor and stromal cells (16). MMP3, also called stromelysin-1, is known to lyse basal membrane collagen and to induce the synthesis of other MMPs. The MMP3 gene is localized on 11q22 adjacent to the MMP1 gene. A single adenine insertion/deletion polymorphism (6A/5A) at the 1171 position of the MMP3 promoter region modulates transcription and local expression of MMP3 (7,8). The influence of this single nucleotide polymorphism (SNP) on tumor development and invasion is not consistent in different tumor types. It has been associated with the risk of development and lymphatic metastasis of breast cancer (9), but has not been linked to susceptibility to and progression of ovarian cancer (10). In a recent study the MMP3 polymorphism was reported to be a predictive factor of response to neoadjuvant chemotherapy in head and neck squamous cell carcinoma (11).
Esophageal squamous cell carcinoma (ESCC) and gastric cardiac adenocarcinoma (GCA) are two prevalent tumors in China. Expression of MMP1, MMP2 and MMP3 has been closely related to lymph node metastasis, vascular invasion and prognosis in ESCC (1214). Our previous results suggested that a guanine base insertion polymorphism at position 1607 of the MMP1 promoter does not modify susceptibility to and lymphatic metastases of both ESCC and GCA (15). Miao et al. reported that a C
T SNP at position 1306 of the MMP2 promoter was associated with the risk of development but not metastasis of GCA (16). To our knowledge, a relationship between the MMP3 5A/6A polymorphism and risk of occurrence and progression of ESCC and GCA has not been reported so far. Therefore, we conducted a hospital-based casecontrol study in a north China population to assess the effects of the MMP3 SNP on the development and clinical staging in these two tumors.
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Materials and methods
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Subjects
This study included 417 cancer patients (234 with ESCC and 183 with GCA) and 350 healthy individuals without overt cancer. The cases were outpatients for endoscopic biopsy or inpatients for tumor resection in the Fourth Affiliated Hospital, Hebei Medical University, between 2001 and 2003. Histological tumor typing was carried out on the basis of biopsies or resected specimens in the Department of Pathology of the same hospital. All esophageal carcinomas were squamous cell carcinomas. All gastric cardiac carcinomas were adenocarcinomas with their epicenters at the gastroesophageal junction, i.e. from 1 cm above to 2 cm below the junction between the end of the tubular esophagus and the beginning of the saccular stomach (17). The healthy subjects, having no history or diagnosis of cancer or genetic disease, were recruited from individuals who visited the same hospital for physical examination between 2001 and 2003. Among 385 invited subjects, 35 (9.1%) refused to join the epidemiology study or give blood samples and therefore were excluded. All of the cancer patients and control subjects were unrelated Han nationality from Shijiazhuang city or the surrounding region. Information on TNM staging was available for 131 ESCC and 94 GCA patients from hospital records and pathological diagnosis. Information on sex, age, smoking habit and family history was obtained from cancer patients and healthy controls by interview conducted by two professional researchers. For smoking habit, former and present smoking status, the number of cigarettes smoked per day and the time of starting and quitting were determined. The participants were also asked about any family history of cancer, including if there had been/were cancer patients in their family, the relationship of the cancer patients to the participant and what type of cancer they had. The definitions of smoker and positive family history of upper gastrointestinal cancers (UGIC) were as described before (18,19). Briefly, individuals who formerly or currently smoked 5 cigarettes/day for at least 2 years were defined as smokers. Individuals with at least one first degree relative or at least two second degree relatives having esophageal/cardiac/gastric cancer were defined as having a family history of UGIC. The study was approved by the Ethics Committee of Hebei Cancer Institute and informed consent was obtained from all subjects.
DNA extraction
Five milliliters of venous blood from each subject was drawn into Vacutainer tubes containing EDTA and stored at 4°C. Genomic DNA was extracted within 1 week after sampling using proteinase K (Merck, Darmstadt, Germany) digestion followed by a salting out procedure according to the method published by Miller et al. (20).
MMP3 SNP genotyping
The MMP3 genotype was determined by PCRrestriction fragment length polymorphism assay. The PCR primers used to amplify the MMP3 polymorphism were 5'-GGTTCTCCATTCCTTTGATGGGGGGAAAgA-3' (forward primer) and 5'-CTTCCTGGAATTCACATCACTGCCACCACT-3' (reverse primer) (21). A mutation from A to G at the second nucleotide close to the 3'-end of the forward primer was made to create a Tth111I recognition site in the case of the 5A allele. PCR was performed in a 20 µl volume containing 100 ng DNA template, 2.0 µl of 10x PCR buffer, 1.5 mmol MgCl2, 1 U Taq DNA-polymerase (BioDev-Tech, Beijing, China), 200 µmol dNTPs and 200 nmol each primer. The PCR cycling conditions were 5 min at 94°C followed by 35 cycles of 30 s at 94°C, 30 s at 65°C and 30 s at 72°C, with a final step at 72°C for 5 min to allow for complete extension of all PCR fragments. An 8 µl aliquot of PCR product was subjected to digestion at 65°C for 4 h in a 10 µl reaction containing 10 U Tth111I (TakaRa Biotechnology, Dalian, China) and 1x reaction buffer. After digestion, the products were separated on a 3% agarose gel stained with ethidium bromide. As a result, the 5A alleles were represented by DNA bands of 97 and 32 bp and the 6A alleles by a DNA band of 129 bp, whereas the heterozygotes displayed a combination of both alleles (129, 97 and 32 bp) (Figure 1). For a negative control, distilled water instead of DNA was used in the reaction system for each PCR. For 10% of the samples the genotyping was repeated for quality control, and all of the results matched the original ones.

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Fig. 1. MMP3 5A/6A genotyping by PCRrestriction fragment length polymorphism. The PCR products were digested with Tth111I restriction enzyme and subjected to electrophoresis on a 3% agarose gel. 1, 100 bp DNA molecular marker; 2 and 6, 5A/6A genotype; 3, 5A/5A genotype; 4 and 5, 6A/6A genotype.
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Statistical analyses
Statistical analysis was performed using the SPSS12.0 software package (SPSS, Chicago, IL). HardyWeinberg analysis was performed to compare the observed and expected genotype frequencies using the
2 test. Comparison of the MMP3 genotype distribution in the study groups was performed by means of two-sided contingency tables using the
2 test. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated using an unconditional logistic regression model and adjusted for age and sex. A probability level of 5% was considered significant for all statistical analyses.
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Results
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The demographic distribution of cancer patients and healthy controls is shown in Table I. The mean age of ESCC cases was 54.1 ± 10.2 years (range 3476), of GCA cases 55.0 ± 10.5 years (range 3776) and of controls 51.7 ± 10.7 years (range 3068). The gender distributions in ESCC and GCA patients (72.2 and 73.2% men) were comparable to that in healthy controls (65.4% men). Information on smoking status from 70 healthy individuals, 44 ESCC and 17 GCA patients was unavailable and family history of UGIC from 221 healthy controls, 50 ESCC and 25 GCA patients was unclear or was not recorded. The proportion of smokers among ESCC patients was not significantly different from that in healthy controls (50.5 versus 42.7%,
2 = 2.793, P = 0.10). However, smokers were significantly more frequent among GCA patients (55.4%) than among healthy controls (
2 = 6.77, P = 0.01). Therefore, smoking significantly increased the risk of development of GCA (age- and sex-adjusted OR = 1.64, 95% CI = 1.122.38). In addition, the frequency of a positive family history of UGIC among ESCC (30.4%) and GCA (39.7%) patients was significantly higher than that in healthy controls (4.7%) (
2 = 31.74 and 47.87, respectively, P < 0.0001). Thus, a family history of UGIC significantly increased the risk of developing ESCC (age- and sex-adjusted OR = 7.89, 95% CI = 3.2515.49, P < 0.0001) and GCA (age- and sex-adjusted OR = 13.24, 95% CI = 5.9826.40, P < 0.0001). Among 131 ESCC and 94 GCA patients with available TNM information, invasion of adjacent structures was reported in 54 and 33 cases and lymphatic metastasis in 59 and 46 cases, respectively. No distant metastasis was reported in either ESCC or GCA patients.
All of the recruited samples were successfully genotyped for the MMP3 polymorphism. The genotype distribution among ESCC and GCA patients and healthy controls did not significantly deviate from that expected for a HardyWeinberg equilibrium (
2 = 4.38, 0.16 and 0.60, P = 0.11, 0.93 and 0.74, respectively). The MMP3 genotype distribution was not correlated with gender and age in cancer patients or healthy controls (data not shown). In healthy controls the frequencies of the 6A/6A, 5A/6A and 5A/5A genotypes were 67.7, 30.0 and 2.3%, whereas the frequencies of the 6A and 5A alleles were 82.7 and 17.3%, respectively. The overall genotype and allelotype distributions in ESCC and GCA patients were not significantly different from that in healthy controls (
2 = 3.22 and 3.01, P = 0.20 and 0.22, respectively) (Table II). However, stratification analysis showed that smoking individuals with the 5A/6A genotype were significantly more common among ESCC patients than among healthy controls (36.5 versus 23.3%,
2 = 6.19, P = 0.01). Conversely, the genotype distributions in non-smoking ESCC patients and healthy controls were not significantly different. Since 5A homozygotes were very rare in both cancer patients and controls, we analyzed the relative risk of the 5A/5A genotype in combination with the 5A/6A genotype. Thus, in smokers the MMP3 heterozygous genotype or genotypes with at least one 5A allele (5A/6A + 5A/5A) significantly increased the risk of developing ESCC, compared with the 6A/6A genotype (age- and sex-adjusted OR = 2.12 and 1.95, 95% CI = 1.163.90 and 1.083.53, respectively). However, a significant difference in MMP3 genotype distribution between GCA patients and healthy controls was not observed in a stratification analysis according to smoking status (Table II).
Since a family history of UGIC has been shown to significantly increase the risk of development of ESCC and GCA, it is reasonable to speculate that there might be differences in genetic susceptibility between familial aggregated and sporadic cancer patients. However, in contrast to our expectation, the genotype distribution in ESCC and GCA patients, either with or without a family history of UGIC, did not show a significant deviation from that in healthy controls (Table II).
To investigate the significance of MMP3 genotyping in the progression of ESCC and GCA, the influence of the MMP3 polymorphism on the depth of tumor invasion and the occurrence of lymphatic metastasis was analyzed in 131 ESCC and 94 GCA patients whose clinical information was available. The allelotype and genotype distributions of the MMP3 SNP in both cancer patients with and without information on TNM were not significantly different (data not shown). Correlation of the MMP3 polymorphism with the depth of tumor invasion (with or without involvement of adjacent structures) was not observed in either tumor type (data not shown). However, as shown in Table III, the genotypes with at least one 5A allele (5A/5A or 5A/6A) were significantly more frequent in patients with lymphatic metastasis than that in lymph node-negative ones for ESCC (45.8 versus 27.8%,
2 = 4.56, P = 0.03). Therefore, ESCC patients with the 5A allele have a >2-fold higher possibility of lymphatic metastasis, compared with those with the 6A/6A genotype (age- and sex-adjusted OR = 2.24, 95% CI = 1.074.69). In contrast, the frequencies of the 5A/5A + 5A/6A genotypes in GCA patients with or without lymphatic metastasis were similar (28.3 versus 27.1%,
2 = 0.02, P = 0.90). Thus, no influence of the MMP3 SNP on lymphatic metastasis of GCA was observed in this study.
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Discussion
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The present study supports the hypothesis that an adenine insertion/deletion polymorphism in the MMP3 promoter region may modify the risk of development and lymphatic metastasis of ESCC. However, this polymorphism may not be associated with susceptibility and clinical staging in GCA. GCA, which was formerly classified as esophageal cancer or gastric cancer by the cancer registry in high incidence regions of China, has been diagnosed as an independent cancer type in recent years, facilitated by early endoscopic screening and improvements in pathologic diagnosis. Since epidemiological studies have shown that ESCC and GCA may share similar etiological factors (2225), genetic studies may help to explain why individuals exposed to similar risk factors develop different kinds of tumors. Although it has been reported that several polymorphic genes, such as methylene tetrahydrofolate reductase (26,27), NAD(P)H:quinone oxidoreductase (28) and Cyclin D1 (19), may modify the risk of ESCC and GCA in similar manners, the present study suggests that at least some polymorphisms, including the MMP3 promoter SNP, may play different roles in the development and progression of these two tumor types.
The present study shows that the role of the MMP3 5A allele in the risk of development of ESCC was significant only in current or ex-smokers, suggesting that MMP3 expression may interact with the metabolic changes induced by smoking and influence the susceptibility to ESCC. This explanation is supported by a report from Yu et al., in which an additive interaction between the MMP2 promoter polymorphism and smoking in elevation of the risk of lung cancer was observed (29). However, the exact mechanism of this interaction needs to be explored in further experiments. In addition, the dosage effect of smoking alone or in combination with the MMP3 polymorphism on susceptibility to ESCC and GCA, which was not analyzed in this study because of the sample size, also need to be further investigated.
Invasion of surrounding structures and lymphatic metastasis are the main factors influencing the prognosis and survival of upper gastrointestinal tumor patients. The finding that genotypes with at least one MMP3 5A allele may increase the risk of lymphatic metastasis in ESCC suggests that patients carrying the 5A allele may need to be treated more actively by lymph node resection and may need trimodality treatment after surgery. In contrast, MMP3 genotype may not be used as a stratification marker in predicting lymphatic metastasis of GCA. Although clinical data in this study were only available for a subset of cancer patients, the similar MMP3 polymorphism distributions in cancer patients with and without information on TNM staging suggests that a chance finding due to selection bias may not be the explanation for this result.
The association between the MMP3 SNP and the risk of development and metastasis of ESCC is consistent with a report by Ghilardi et al., which showed that the frequency of the MMP3 5A allele was significantly higher in breast cancer patients than in controls and that 5A homozygotes had a 2.4-fold higher risk of metastasis of this cancer (9). In a recent study Krippl et al. also observed a linkage between the 5A/5A genotype and increased risk of lymphatic metastasis in breast cancer, although no association of the MMP3 polymorphism with susceptibility to the tumor was shown in their study (30). No association between the 5A/5A genotype and the development and lymphatic metastasis of ESCC was observed in the present study, probably due to the prevalence of the 5A homozygote in northern Chinese (2.3%), which is much lower than in Caucasians (20 and 23.3% in the above studies). The role of the MMP3 5A allele in tumor risk and invasion may be directly related to its 2-fold increased activity in transcription (7,8). MMP3 expression may also activate other MMPs, such as MMP1 and MMP9 (31,32). Overexpression of the MMPs may increase local invasion and metastasis by degrading the ECM and facilitating tumor cell infiltration of the basal membrane, also involving the surrounding lymphatic vessels (35). MMPs may also be involved in the early stages of tumor development by regulating cell growth, apoptosis and vessel formation, through cleaving a diverse group of substrates other than structural components of the ECM, which include growth factor-binding proteins, growth factor precursors, receptor tyrosine kinases, cell adhesion molecules and other proteinases (3338). In addition, because many cells have receptors for structural ECM components, cleavage of ECM proteins by MMPs may affect cellular signaling and functions, which may promote tumor cell growth and migration (3,39). Taken together, overexpression of MMPs induced by the gene polymorphism may promote cancer development and progression in several ways, resulting in the creation and maintenance of the microenvironment for tumor cell proliferation, migration and invasion.
The divergent role of the MMP3 SNP in ESCC and GCA may be related to the different pathologies of these two tumors. Expression of MMP3 has been reported to play an important role in tumor invasion and metastasis in ESCC (14), whereas no significance of MMP3 in GCA has been reported so far. Since GCA is pathologically consistent with gastric cancer, investigations of gastric cancer may give clues to explain the present results. Murray et al. reported that although a large proportion of gastric cancers express MMP2 (94%), MMP1 (73%) and MMP9 (70%), MMP3 was only present in 27% of tumors (39). Therefore, the present results, together with the results for gastric cancer, suggest that MMP3 expression may not be an important event in GCA. However, since this was a retrospective study with a relatively small sample size, which makes it difficult to draw final conclusions, further investigations with a larger sample need to be performed to clarify the effects of the MMP3 SNP on the development and prognosis of ESCC and GCA.
In conclusion, the present study suggests that a single adenine insertion/deletion polymorphism at the 1171 position in the MMP3 promoter region may modify the risk of development and lymphatic metastasis in ESCC but not in GCA.
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Acknowledgments
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We gratefully acknowledge Mrs Liwei Zhang, Mrs Xiaoqing Guo, Mr Ming He and Mr Mingli Wu of the Fourth Affiliated Hospital of Hebei Medical University, China, for their assistance in recruiting study subjects. This work was supported by grants from the National Natural Science Foundation (no. 30371591) and the Educational Department of Hebei Province (no. 2001150), China
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Received May 30, 2004;
revised July 19, 2004;
accepted August 10, 2004.