Abstract
Purpose
Matrix metalloproteinase-9 (MMP-9, gelatinase B) plays a key role in cancer invasion and metastasis by degradating the extracellular matrix (ECM) and basement membrane barriers. A cytosine (C)-thymidine (T) single nucleotide polymorphism (SNP) at position –1562 in the MMP-9 promoter is reported to affect expression of this gene. The purpose of this study was to investigate the relation between the –1562 C/T polymorphism and the development and progression of gastric cancer.
Methods
The study population included 177 gastric cancer patients and 224 healthy control subjects. The SNP in the MMP-9 promoter was analyzed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and sequencing. Genotype frequencies were compared between patients and controls, and the association of genotypes with clinicopathological features was studied.
Results
Genotype frequencies in gastric cancer patients were similar to those in control subjects (P = 0.223). However, significant association was found between degree of tumor invasion, clinical stage, and lymphatic invasion and the MMP-9 polymorphism in gastric cancer patients (P<0.05, for each).
Conclusions
Our results indicate that the T allele in the MMP-9 promoter is associated with the invasive phenotype of gastric cancer.
Keywords: MMP-9, SNP, Gastric cancer, Depth of tumor invasion, Lymphatic invasion
Introduction
Gastric cancer is one of the most common malignancies in the world and is the leading cause of death in Japan. Poor prognosis reflects the invasive and metastatic capabilities of cancer cells. Degradation of the extracellular matrix (ECM) and basement membrane barriers by matrix metalloproteinases (MMPs) plays an important role in tumor invasion and metastasis (Forget et al. 1999; Kohn and Liotta 1995; Liotta et al. 1991). MMP-9 (92-kDa gelatinase, type IV collagenase) is a member of the family of MMP genes, which encode zinc-dependent enzymes that break down ECM through the degradation of type IV collagen (Nagase and Woessner 1999), and promote tumor cell invasion. The prognostic value of MMP-9 expression by tumor tissues has been reported in relation to a variety of cancers (McDonnell and Matrisian 1990; Kallakury et al. 2001; Baker and Leaper 2003; Tanioka et al. 2003; Ozalp et al. 2003; Sakata et al. 2004).
Zhang et al. (Zhang et al. 1999) reported that a cytosine (C)-to-thymidine (T) transition at nucleotide −1562 in the MMP-9 gene promoter generates low-activity (C/C) and high-activity (C/T, T/T) promoter genotypes, which influence gene transcription. This polymorphism is associated with the severity of coronary atherosclerosis in patients with coronary artery disease. However, there have been no studies of the relation between this polymorphism and malignancies. Various genetic and epigenetic alterations are associated with gastric carcinoma (Yasui et al. 2000; Oue et al. 2002; Oue et al. 2003). We previously reported that several polymorphisms are significantly associated with gastric cancer (Kuraoka et al. 2003; Matsumura et al. 2004). With respect to the role of the C/T polymorphism in transcriptional activity and degradation of ECM, we hypothesized that this polymorphism might also act as a genetic modifier in the development and progression of gastric cancer. Therefore, we conducted a case-control study to investigate the association between the different MMP-9 promoter alleles and gastric cancer. Moreover, we examined the relation between the C/T polymorphism and the clinicopathological features of gastric cancer patients.
Materials and methods
Samples
A total of 401 peripheral blood samples from 224 healthy control subjects and 177 gastric cancer patients were used in the present study. Control subjects were randomly selected from among individuals visiting hospitals for regular health checks or because of symptoms such as appetite loss or epigastralgia. Control subjects were confirmed to be free of malignancy by gastrointestinal endoscopy and biopsy. Gastric cancer patients underwent surgical or endoscopic mucosal resection (EMR) at Hiroshima University Hospital or Hofu Institute of Gastroenterology. Gastric cancer patients were 129 men and 48 women; the median age was 65.1±11.7 years. Gastric cancer was classified histologically according to the criteria of Lauren (Lauren 1965); 103 patients had intestinal type gastric cancer, and 74 patients had diffuse type. Intestinal type and diffuse type correspond to well-differentiated type and poorly differentiated type, respectively, of the histological classification system of the Japanese Gastric Cancer Association (Japanese Gastric Cancer Association 1998). Gastric cancer patients were grouped according to TNM classification (Sobin and Wittekind 2002) on the basis of the postoperative histopathological evaluation. Moreover, patients were assigned to two subgroups on the basis of whether they were positive or negative for lymphatic invasion or venous invasion at the time of diagnosis (Japanese Gastric Cancer Association 1998). All patients and control subjects gave written informed consent prior to enrollment in the study. The Human Genome Research Ethics Screening Committee of Hiroshima University School of Medicine approved the study.
DNA extraction and polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) analysis
A genomic DNA purification kit (Promega, Madison, Wisc., USA) and a QIAamp 96 DNA Blood kit (QIAGEN, Valencia, Calif., USA) were used for DNA extraction. PCR- RFLP assay was used to determine MMP-9 genotypes as previously described (Zhang et al. 1999). To analyze the –1562 C/T polymorphism, we amplified a region of the MMP-9 promoter with forward primer 5’-GCC TGG CAC ATA GTA GGC CC-3’ and reverse primer 5’-CTT CCT AGC CAG CCG GCA TC −3’ (Zhang et al. 1999). The target sequence was amplified in a 25-μl reaction volume containing 10–20 ng of genomic DNA, 0.2 μM dNTP, 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 2 mM MgCl2, 0.3 μM of each primer, and 0.75 units of AmpliTaq Gold (Perkin-Elmer, Norwalk, Conn., USA). Amplification conditions were an initial activation step of 94 °C for 10 min followed by 35 cycles of denaturation at 94 °C for 30 s, annealing at 59 °C for 30 s, and extension at 72 °C for 30 s. The 435 bp fragment was then digested with SphI (New England BioLabs, Beverly, Mass., USA) overnight at 37 °C. SphI does not digest the C allele (435 bp) but generates 188 bp and 247 bp fragments for the T allele. Digests were separated by electrophoresis on 2.5% NuSieve 3:1 agarose (FMC BioProducts, Rockland, Me., USA) gels for 60 min at 100 V. Heterozygotes had a combination of both alleles (435 bp, 247 bp, and 188 bp bands).
Sequencing analysis of PCR products
The PCR products were purified and cloned into pCR2.1 (Invitrogen, Carlsbad, Calif., USA). Plasmid DNA was extracted from individual clones by alkaline lysis plasmid minipreparation. The cloned PCR fragments obtained from each sample were sequenced with both M13 reverse and M13 forward primers and the PRISM AmpliTaq DNA Polymerase FS Ready Reaction Dye Terminator Sequencing Kit (PerkinElmer ABI, Foster City, Calif., USA). Reamplified DNA fragments were purified with Centri-Sep Columns (Princeton Separations, Adelphia, N.J., USA) and sequenced with an ABI PRISM 310 Genetic Analyzer (PerkinElmer ABI).
Helicobacter pylori status
Confirmation of H. pylori status was based on combinations of histology, 13C-urea breath test, and serum anti-H. pylori IgG antibody. One hundred and seventeen of 224 healthy control subjects and 73 of 177 gastric cancer patients underwent these examinations. Four biopsy specimens were taken, two from the greater curvature of the antrum and two from the upper body of the stomach. When lesions suspected to be cancerous were noted, additional biopsies were performed. Of these four specimens were fixed in formalin and assessed for H. pylori by Giemsa staining. The cutoff value of 13C-urea breath test was 3.5‰. If one or more test were positive, patient was judged to be infected with H. pylori. If all H. pylori tests were negative, the patient was considered uninfected.
Statistical analysis
Statistical analysis was performed with the use of Fisher’s exact test. P <0.05 was considered statistically significant. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to estimate the risk of association with genotypes. ORs for the genotypes were calculated by the logistic regression model, with adjustments for age and sex; logistic regression analysis was performed for the association between genotypes and clinicopathological factors (SPSS 11.0, SPSS, Chicago, Ill., USA).
Results
Genotyping and genotype distributions in gastric cancer patients and control subjects
We examined the –1562 C/T polymorphism in the MMP-9 gene promoter by PCR-RFLP in gastric cancer patients and control subjects. Three PCR-RFLP patterns were detected (Fig. 1). Patients 2, 4, 6, 7, 8, and 9 had a single 435 bp band (C/C genotype), and patient 5 had 247 bp and 188 bp bands (T/T genotype). Patients 1, 3, and 10 had all three bands, indicating the heterozygous genotype (C/T). Subsequent sequencing of representative cases confirmed the genotypes of patients 2 and 5 (Fig. 2). Distribution of the –1562 C/T polymorphism genotypes in gastric cancer patients and control subjects is shown in Table 1. Distribution of genotypes in controls was in good agreement with Hardy-Weinberg equilibrium; distribution in cases also agreed with Hardy-Weinberg equilibrium. Frequency of the T allele (C/T and T/T) was similar between gastric cancer patients (24.9%) and control subjects (30.3%; P = 0.22, OR=0.75, 95% CI=0.48–1.18). In addition, genotype frequencies (C/C vs C/T+T/T) did not differ by sex, age, or H. pylori status.
Fig. 1.
PCR-RFLP analysis of the –1562 C/T polymorphism in ten patients with gastric cancer. The ethidium bromide-stained 2.5% NuSieve 3:1 agarose gel used for genotyping is shown. The target region (435 bp) of the MMP-9 gene promoter was PCR amplified and digested with SphI, which cleaved the T allele to generate two fragments (247 bp and 188 bp) are indicated, but did not cut the C allele (435 bp). Numbers above the panel are case numbers. Genotypes are indicated below each case.
Fig. 2.
Representative electropherogram for each genotype for the –1562 C/T polymorphism of MMP-9. Genotype of the SNP was C/C in case 2 and T/T in case 5.
Table 1.
MMP-9 Genotype distributions in study subjects (OR odds ratio, CI confidence interval).
| Controlsa (%) | Patients (%) | Crude ORc | ||
|---|---|---|---|---|
| (n = 224) | (n = 177) | P valueb | (95% CI) | |
| Overall | ||||
| C/C | 156 (69.7) | 133 (75.1) | ||
| C/T | 63 (28.1) | 38 (21.5) | ||
| T/T | 5 (2.2) | 6 (3.4) | 0.223 | 0.758 (0.486–1.182) |
| Sex | ||||
| Male | ||||
| C/C | 73 (68.2) | 97 (75.2) | ||
| C/T | 32 (29.9) | 28 (21.7) | ||
| T/T | 2 (1.9) | 4 (3.1) | 0.235 | 0.708 (0.400–1.252) |
| Female | ||||
| C/C | 83 (70.9) | 36 (75.2) | ||
| C/T | 31 (26.5) | 10 (20.8) | ||
| T/T | 3 (2.6) | 2 (4.2) | 0.597 | 0.813 (0.378–1.748) |
| Age (years) | ||||
| <65 | ||||
| C/C | 78 (67.8) | 54 (71.1) | ||
| C/T | 35 (30.4) | 20 (26.3) | ||
| T/T | 2 (1.8) | 2 (2.6) | 0.636 | 0.858 (0.456–1.613) |
| ≥65 | ||||
| C/C | 78 (71.6) | 79 (78.2) | ||
| C/T | 28 (35.7) | 18 (17.8) | ||
| T/T | 3 (2.7) | 4 (4.0) | 0.267 | 0.701 (0.373–1.316) |
| H. pylori infection | ||||
| Negative | n = 42 | n = 29 | ||
| C/C | 32 (76.2) | 25 (86.2) | ||
| C/T | 9 (21.4) | 3 (21.7) | ||
| T/T | 1 (2.4) | 1 (3.5) | 0.297 | 0.512 (0.143–1.827) |
| Positive | n = 75 | n = 44 | ||
| C/C | 55 (73.3) | 32 (72.7) | ||
| C/T | 19 (25.3) | 12 (27.3) | ||
| T/T | 1 (1.4) | 0 (0.0) | 0.942 | 1.031 (0.446–2.383) |
aObserved genotype distribution of controls was in agreement with Hardy-Weinberg equilibrium
bAssociation was analyzed by Fisher’s exact test. P are values for C/T+T/T genotype relative to C/C genotype
cOdds ratios are for C/T+T/T genotypes relative to C/C genotype
Association between genotypes and clinicopathological features
We next analyzed the association between the –1562 C/T genotypes and clinicopathological features among gastric cancer patients (Table 2). Gastric cancer patients with the T allele (C/T and T/T) showed deeper invasion over the submucosal (sm) layer than did patients with the C/C genotype (crude OR=2.61, 95% CI=1.07–6.33). Advanced-stage gastric cancers were significantly more frequent in patients with the T allele (C/T and T/T) than in patients with the C/C genotype (stage I vs stages II, III, and IV, crude OR=2.25, 95% CI=1.12–4.50). Furthermore, there was a significant difference in genotype distribution (C/T+T/T vs C/C) with respect to lymphatic invasion (lymphatic invasion positive vs negative, crude OR=2.27, 95% CI=1.09–4.73), and risk of venous invasion of gastric cancer was increased (enhanced risk=1.98) in patients with the T allele (venous invasion positive vs negative, crude OR=1.98, 95% CI=0.99–3.96). Histological classification (diffuse type vs intestinal type) and lymph node metastasis was not significantly associated with genotype. Logistic regression analysis revealed that genotype associations with depth of tumor invasion (adjusted OR=2.61, 95% CI=1.07–6.34), TNM classification (adjusted OR=2.26, 95% CI=1.12–4.54), and lymphatic invasion (adjusted OR=2.27, 95% CI=1.09–4.73) remained significant even after adjustments for age and sex.
Table 2.
Association between –1562 C/T polymorphism in MMP-9 promoter and clinicopathological features of gastric cancer.
| Genotype (%) | ORa (95%CI) | ||||
|---|---|---|---|---|---|
| C/C | C/T | T/T | Crude | Adjustedb | |
| Age (year) | |||||
| <65 (n = 76) | 54 (71.1) | 20 (26.3) | 2 (2.6) | ||
| ≥65 (n = 101) | 79 (78.2) | 18 (17.8) | 4 (4.0) | 0.683 | |
| (0.345–1.356) | |||||
| Sex | |||||
| Male (n = 129) | 97 (75.2) | 28 (21.7) | 4 (3.1) | ||
| Female (n = 48) | 36 (75.0) | 10 (20.8) | 2 (4.2) | 0.990 | |
| (0.460–2.129) | |||||
| Histological classificationc | |||||
| Intestinal (n = 103) | 81 (78.6) | 18 (17.5) | 4 (3.9) | ||
| Diffuse (n = 74) | 52 (70.3) | 20 (27.0) | 2 (2.7) | 1.558 | 1.601 |
| (0.784–3.093) | (0.778–3.297) | ||||
| P = 0.201 | |||||
| Depthd | |||||
| m (n = 51) | 44 (86.3) | 6 (11.8) | 1 (1.9) | ||
| sm ~ (n = 126) | 89 (70.6) | 32 (25.4) | 5 (4.0) | 2.613 | 2.610 |
| (1.079–6.331) | (1.074–6.340) | ||||
| P = 0.034 | |||||
| Lymphatic invasione | |||||
| Negative (n = 78) | 65 (83.3) | 12 (15.4) | 1 (1.3) | ||
| Positive (n = 99) | 68 (68.7) | 26 (26.3) | 5 (5.0) | 2.279 | 2.274 |
| (1.097–4.736) | (1.092–4.736) | ||||
| P = 0.028 | |||||
| Venous invasione | |||||
| Negative (n = 95) | 77 (81.1) | 16 (16.8) | 2 (2.1) | ||
| Positive (n = 82) | 56 (68.3) | 22 (26.8) | 4 (4.9) | 1.986 | 1.984 |
| (0.994–3.969) | (0.993–3.967) | ||||
| P = 0.053 | |||||
| Lymph node metastasis | |||||
| N (-) (n = 114) | 89 (78.1) | 22 (19.3) | 3 (2.6) | ||
| N (+) (n = 63) | 44 (69.8) | 16 (25.4) | 3 (4.8) | 1.537 | 1.537 |
| (0.765–3.088) | (0.761–3.102) | ||||
| P = 0.230 | |||||
| TNM classificationf | |||||
| Stage I (n = 99) | 81 (81.8) | 16 (16.2) | 2 (2.0) | ||
| Stage II, III, IV (n = 78) | 52 (66.7) | 22 (28.2) | 4 (5.1) | 2.250 | 2.260 |
| (1.123–4.507) | (1.124–4.547) | ||||
| P = 0.022 | |||||
| H. pylori infectiong | |||||
| Negative (n = 29) | 25 (86.2) | 3 (10.3) | 1 (3.5) | ||
| Positive (n=44) | 32 (72.7) | 12 (27.3) | 0 (0.0) | 0.427 | 0.416 |
| (0.123–1.484) | (0.117–1.473) | ||||
| P=0.174 | |||||
aOdds ratios (ORs) and 95% confidence intervals (CIs) for clinicopathological features with reference to the MMP-9 promoter polymorphism (C/T+T/T to C/C genotypes)
bAdjusted for age and sex, with a logistic regression model
cGastric cancer classified histologically according to the criteria of Lauren
dDepth of tumor invasion. (m tumour without invasion of the submucosa. sm~ tumour invades over the submucosal layer)
eLymphatic invasion and venous invasion classified according to the criteria of Japanese Classification of Gastric Carcinoma, 2nd English edn
fTNM grades were according to the criteria of the TNM Classification of Malignant Tumors, 6th edn
gH. pylori status was based on histology, 13C-urea breath test, and serum anti-H. pylori IgG antibody
Discussion
In the present study, we examined whether risk of gastric cancer is associated with the –1562 C/T polymorphism in the promoter of MMP-9 in a Japanese population. It has been suggested that carcinogenesis is a multicellular and multistage process in which breakdown of the microenvironment is required for conversion of normal tissue to tumor (Park et al. 2000). Although we hypothesized that the MMP-9 polymorphism alters the microenvironment and may be involved in the process of carcinogenesis, the allele frequencies in the gastric cancer patients were similar to those in controls. Our findings suggest that the T allele does not enhance susceptibility to the development of gastric cancer. In contrast, we found a significant association between this polymorphism and clinicopathological features, specifically depth of tumor invasion, TNM classification, and lymphatic invasion. The T allele was detected more frequently in patients with advanced-stage gastric cancers than in those with the C/C genotype (OR=2.26). Moreover, lymphatic invasion was significantly enhanced in gastric cancer patients with the T allele. However, lymph node metastasis showed no significantly associated with genotype. Establishment of metastasis requires the serial processes such as invasion, migration, implantation, and regrowth of cancer cells at the metastatic site. The MMP-9 polymorphism may affect the initial invasion step of lymph node metastasis. The present findings support our hypothesis that the –1562 C/T polymorphism may have a profound impact on progression and invasion of gastric cancer. To our knowledge, this is the first study to investigate the association of the –1562 C/T polymorphism of MMP-9 with development and malignant phenotypes of gastric cancer.
The association between the MMP-9 polymorphism and invasive phenotype of gastric cancer is consistent with the biological function of MMP-9. Overexpression of MMP-9 has been observed in a variety of cancers including gastric cancer, breast cancer, prostate cancer, brain cancer, melanoma, and lymphoma (Murray et al. 1998; Hujanen et al. 1994; Jones et al. 1999; Rao et al. 1993; Sehgal et al. 1996; Chicoine et al. 2002). In gastric cancer, expression of MMP-9 is associated with pathological features such as TNM stage, lymphatic invasion, and tumor depth (Zhang et al. 2003). Furthermore, expression of MMP-9 is associated with poor prognosis in renal cell carcinoma patients (Kallakury et al. 2001). In breast cancer patients, plasma MMP-9 activity is also associated with prognosis (Baker and Leaper 2003). These findings clearly indicate that MMP-9 plays an important role in tumor progression and invasion. Moreover, the C/T polymorphism in MMP-9 has functional significance. The MMP-9 promoter with the T allele shows significantly higher transcriptional activity than the C allele in cultured macrophages, and this polymorphism influences the atherosclerotic phenotype (Zhang et al. 1999). The MMP-9 gene promoter contains binding sites for AP-1, NF-kB, Sp-1, and Ets transcription factors (Gum et al. 1996). In particular, Ets-1 expression is upregulated together with MMP-9 (Behrens et al. 2001), and this upregulation correlates with tumor invasion in gastric cancer (Nakayama et al. 1996). This polymorphism is located within a transcription factor binding site, and that changing the allele may affect transcription factor binding and therefore expression of MMP-9 (Zhang et al. 1999). We also found the MMP-9 polymorphism to be associated with depth of tumor invasion, lymphatic invasion, and TNM classification of gastric cancer. Taken together, these results suggest that the T allele may affect expression of MMP-9 in gastric cancer, increasing ECM degradation and leading to subsequent invasion of cancer cells.
Conclusion
In conclusion, our findings suggest that the T allele of the MMP-9 promoter may affect expression of MMP-9 and is closely related to the invasive phenotype of gastric cancer. Recently, in vitro studies showed that MMP-9 production is increased more than two times by tumor necrosis factor-alpha (TNF-alpha) (Ferrand et al. 2002) and more than seven times by gastrin (Wroblewski et al. 2002). Moreover, Chicoine et al. (Chicoine et al. 2002) reported that MMP-9 expression is controlled by the methylation status of the MMP-9 promoter. Further studies of the association between the levels of MMP-9 expression and the –1562 C/T polymorphism in gastric cancer patients are needed with increased numbers of cases to confirm our findings.
Acknowledgements
We thank Masayoshi Takatani and Mutsumi Ueda, Department of Molecular Pathology, Hiroshima University Graduate School of Biomedical Sciences, for their excellent technical assistance and advice
Abbreviations
- MMP-9
Matrix metalloproteinase-9
- SNP
Single nucleotide polymorphism
- C
Cytosine
- T
Thymidine
- RFLP
Restriction fragment length polymorphism
- ECM
Extracellular matrix
- PCR
Polymerase chain reaction
- OR
Odds ratio
- CI
Confidence interval
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