Research ArticleExperimental Studies

Association of Matrix Metallopeptidase-2 Genotypes With Risk of Gastric Cancer in Taiwan

CHUN-KAI FU, MEI-CHIN MONG, CHIEN-CHIH YU, MEI-DUE YANG, ZHI-HONG WANG, YA-CHEN YANG, JAW-CHYUN CHEN, JEN-SHENG PEI, NING-YI HSIA, CHIA-WEN TSAI, WEN-SHIN CHANG and DA-TIAN BAU
Anticancer Research April 2022, 42 (4) 1749-1755; DOI: https://doi.org/10.21873/anticanres.15651

Abstract

Background/Aim: Matrix metalloproteinase-2 (MMP-2) plays a critical role in the regulation of the extracellular matrix; however, its genotypes have seldom been examined in gastric cancer (GC). This study aimed to investigate the contribution of MMP-2 promoter -1306 (rs243865) and -735 (rs2285053) genotypes to GC risk in a cohort of Taiwanese individuals. Materials and Methods: This study included 121 GC cases and 363 age- and sex-matched controls. The genotypes of MMP-2 were determined by typical polymerase chain reaction-restriction fragment length polymorphism. Results: The genotypic and allelic frequency analysis showed that MMP-2 rs243865 variant genotypes decreased the risk of GC. Stratification analysis showed that MMP-2 rs243865 genotypes associate with smoking, alcohol drinking, and Helicobacter pylori infection status to confer personal susceptibility to GC. There is no such association for MMP-2 rs2285053 genotype with GC risk. Conclusion: The MMP-2 rs243865 genotypes may serve as a novel predictive marker for GC personal susceptibility among Taiwanese.

Key Words:

Epidemiologically, gastric cancer (GC) is one of the major causes of cancer-related death in the world and the third leading cause of global cancer-related deaths (1). The detailed mechanisms of gastric carcinogenesis remain largely unknown and are believed to be complicated. Several environmental factors such as imbalanced diets, Helicobacter pylori (H. pylori) infection, and pre-existing disorders (e.g., pernicious anemia, atrophic gastritis, and/or intestinal polyps) have been shown to contribute to higher GC risk (2). Inherited genetic variations may determine personal susceptibility to GC, however, they are largely unknown (3–6). In the past recent decades, after the decoding of the human genome, mounting studies aiming at investigating the associations of specific genes with the risk of GC have been performed (5, 7–11).

The extracellular matrix (ECM) is closely associated with the homeostasis of the micro-environment, and its imbalances may associate with cancer initiation and development (12, 13). Noticeably, matrix metalloproteinases (MMPs) are usually over-expressed in the stromal compartments of ECM and associate with metastatic behaviors via degradation of the ECM components (13–15). In literature, MMPs have been shown to be related to tumor metastasis (16), and mounting evidence has revealed that MMP-2 plays a central part in inducing the metastatic potential of a variety of cancers, including glioma, ovarian, pancreatic, and colorectal cancer cells (17–20). In regard to GC, the levels of the precursor form of MMP-2 (proMMP-2) in the serum have been found to be higher in GC patients compared to those in non-cancer healthy controls in Japan (21). In addition, the expression levels of MMP-2 were significantly higher in tumor sites in comparison with the adjacent histologically intact gastric mucosa in 80% of patients with GC in Russia (22). Strangely, the percentage of MMP-2 and TIMP-2 was higher in GC and inflammatory cells compared to that in normal tissues, while serum levels of MMP-2 and TIMP-2 were statistically lower in GC patients in comparison to those in healthy subjects in Netherlands (23). The inconsistency seen regarding MMP-2 expression makes its contribution to the development of GC largely unclear.

MMP-2 is located on chromosome 16q21, coding for an endopeptidase that is expressed in a variety of tissues (24–26). In literature, it has been shown that at least MMP-2 -1306 (rs243865) and -735 (rs2285053) can affect its mRNA and protein expression levels, and eventually increase the metastatic potential of several types of cancer, including breast, esophageal colorectal, oral cancer, and leukemia (27–31). In 2006, Kubben et al. found that MMP-2 rs243865 genotypes were correlated significantly with its protein expression levels within tumor sites; however, they were neither a good marker for GC susceptibility nor for tumor-related survival in Netherlands (32). In 2010, Alakus et al. reported that MMP-2 rs243865 genotypes were not associated with GC susceptibility or with worse survival rates in Germany (33). In 2015, Zhang et al. announced that MMP-2 rs243865 TT genotype was associated with decreased GC susceptibility, and serum MMP-2 protein levels might be associated with GC susceptibility in China (34). According to the above information, the contribution of MMP-2 genotypes to GC risk is inconsistent in different populations. Therefore, the present genotyping study aimed to examine the contributions of MMP-2 promoter -1306 (rs243865) and -735 (rs2285053) polymorphisms to the risk of GC in Taiwan, and evaluate their association with smoking, alcohol drinking, and H. pylori infection.

Materials and Methods

Collection of GC population. Up to 121 patients diagnosed with GC were recruited at the outpatient clinics of general surgery between 2005 and2007 at the China Medical University Hospital, Taiwan as we have previously reported (9, 10, 35). Briefly, all participants voluntarily provided peripheral blood samples. Matched according to age and sex, 363 healthy individuals as controls were collected artificially from the Health Examination Cohort of the hospital. Characteristics of all participants are concisely summarized in Table I.

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Table I.

Selected characteristics of the control and gastric cancer groups.

MMP-2 genotyping. Genomic DNA was extracted from whole blood within the first 24 h of withdrawal as previously reported (36–38). In the current study, the genotypes of MMP-2 rs243865 and rs2285053 were determined for all the participants by using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the BioRad Mycycler (BioRad, Hercules, CA, USA). The primers for MMP-2 rs243865 were 5’-CTTCCTAGGCTGGTCCTTACTGA-3’ and 5’-CTGAGACCTGAAGAGCTAAAGAGCT-3’ and for MMP-2 rs2285053 5’-GGATTCTTGGCTTGGCGCAGGA-3’ and 5’-GGGGGCTGGGTAAAATGAGGCTG-3’. The PCR reaction was set as: 5 min initial cycle at 94°C; 40 cycles of 94°C for 30 s, 55°C for 30 s, and 72°C for 30 s; and a final extension at 72°C for 10 min. Immediately after the PCR, the DNA adducts were subjected to overnight digestion with the corresponding endonucleases (XspI for MMP-2 rs243865 and HinfI for MMP-2 rs2285053, respectively). Then, each sample was subjected to 3% agarose gel electrophoresis. The procedure was performed by two researchers blindly and independently. The data were 100% concordant to each other.

Statistical analysis. The typical unpaired Student’s t-test was applied to test the continuous index of ages. Pearson’s Chi-square test was applied to compare the distribution of the MMP-2 genotypes among subgroups (n≥5, chi-square without Yates’ correction; n<5, Fisher’s exact test). The associations between the MMP-2 rs243865 and rs2285053 genotypes and childhood GC risk were examined by odds ratios (ORs) and the corresponding 95% confidence intervals (CIs). Any difference with p<0.05 was considered statistically significant.

Results

The selected characteristics of the 121 GC cases and 363 age- and sex-matched controls are summarized in Table I. There was no difference in age and sex between the control and GC case groups (Table I). In addition, there was no difference in the body mass index (BMI) between the two groups (Table I). However, the percentages of cigarette smokers and heavy smokers were higher in the GC group than in the control group (34.7% versus 19.6% and 10.7% versus 1.7%, respectively). Furthermore, the percentages of alcohol drinkers (ever drinkers) and heavy drinkers were higher in the GC case group compared to those in the control group (32.2% versus 23.1% and 9.9% versus 4.4%, respectively). In addition, the percentage of H. pylori infection was higher in GC cases compared to that in controls (70.2% versus 51.8%, respectively). Lastly, regarding tumor location, 14% of tumors were located at the upper part of the stomach, 44.6% at the middle part, and 41.3% at the lower among GC patients (Table I).

The distributions of MMP-2 rs243865 and rs2285053 genotypes among the controls and GC cases are presented in Table II. First, the frequency distributions of both MMP-2 rs243865 and rs2285053 genotypes in the control group fitted well with the Hardy-Weinberg equilibrium (p=0.7325 and 0.2920, respectively). Second, the genetic frequencies of MMP-2 rs243865 were differentially distributed between the case and control groups (p for trend=0.0274). In detail, the CT MMP-2 rs243865 was significantly lower in the GC group than that in the control group (ORs=0.50, 95%CI=0.30-0.85, p=0.0095). The differences were not significant regarding the distribution of the TT genotype between the case and control groups (ORs=0.51, 95%CI=0.11-2.37, p=0.5223). The differential distributions remained statistically significant when the CT and TT genotypes were combined (ORs=0.50, 95%CI=0.30-0.84, p=0.0073). (Table II, top). Third, the distributions of MMP-2 rs2285053 genotypes were not significantly different (p for trend=0.7508) (Table II, bottom).

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Table II.

Distributions of genetic frequencies of MMP-2 polymorphisms among 121 gastric cancer patients and 363 healthy controls.

In order to confirm the results shown in Table II, the distribution of the allelic frequencies of the MMP-2 rs243865 and rs2285053 genotypes was analyzed (Table III). The T allele frequency at MMP-2 rs243865 was 10.4% in the GC patient group, significantly lower than that in the control group (OR=0.55, 95%CI=0.35-0.87, p=0.0103) (Table III, top). On the contrary, the T allele frequencies at MMP-2 rs2285053 were 21.1% and 18.9% in the GC patient and control groups, respectively, showing no statistical significance (OR=1.15, 95%CI=0.80-1.65) (Table III, bottom).

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Table III.

Distributions of allelic frequencies of MMP-2 in gastric cancer case and control groups.

As shown in Table I, cigarette smoking may be an environmental risk factor for GC risk. Thus, we aimed to analyze the interaction of MMP-2 rs243865 and cigarette consumption in relation to the risk of GC (Table IV). Among non-smokers, the CC genotype significantly increased the risk of GC (OR=2.31, 95%CI=1.23-4.32, p=0.0076). The contribution of cigarette consumption alone to GC cancer risk was 3.28-fold for those without the CC genotype MMP-2 rs243865 (95%CI=1.24-8.67, p=0.0129). An additive increasing effect was found for cigarette consumption in association with the CC genotype regarding GC risk (OR=4.26, 95%CI=2.09-8.70, p=0.0001) (Table IV).

View this table:
Table IV.

Combined analysis of MMP-2 genotypes and cigarette consumption in correlation with gastric cancer risk.

In Table I, the data also showed that alcohol drinking may be a risk factor for GC. Thus, we also analyzed the interaction of MMP-2 rs243865 and alcohol drinking in relation to the risk of GC (Table V). Among non-alcohol drinkers, the CC genotype significantly increased the risk of GC (OR=2.61, 95%CI=1.37-4.97, p=0.0027). The contribution of alcohol drinking alone to GC risk was 2.95-fold for those without the CC genotype at MMP-2 rs243865 (95%CI=1.15-7.54, p=0.0202). Similarly, there was an additive increasing effect of cigarette consumption in association with the CC genotype on GC risk (OR=3.30, 95%CI=1.59-6.88, p=0.0010) (Table V).

View this table:
Table V.

Combined analysis of MMP-2 genotype and alcohol consumption in correlation with gastric cancer risk.

The most interesting finding related to the H. pylori infection status. MMP-2 CC genotype was associated with a borderline 1.74-fold increased risk of GC (95%CI=0.74-4.04, p=0.1981). H. pylori infection alone almost associated with an increased risk of GC among those not carrying the CC genotype of MMP-2 rs243865 (OR=1.88, 95%CI=0.74-4.76, p=0.1819). However, H. pylori-infected individuals carrying the CC genotype of MMP-2 rs243865 exhibited a significant increased risk of GC (OR=3.85, 95%CI=1.74-8.52, p=0.0005). The results in Table IV, Table V and Table VI indicated a significant correlation between MMP-2 rs243865 genotype and cigarette smoking, alcohol drinking, and H. pylori infection, in the development of GC.

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Table VI.

Combined analysis of MMP-2 genotypes and H. pylori infection in correlation with gastric cancer risk.

Discussion

In the present study, the association of MMP-2 rs243865 and/or rs2285053 genotypes to Taiwanese GC risk was firstly investigated among 121 GC patients and 363 age- and sex-matched controls. In literature, the variants MMP-2 rs243865 and rs2285053 have been reported to undermine the binding site of transcription factor Sp1, resulting in the suppression of its transcription, and finally in a lower level of MMP-2 expression (39). One of the highlights of the current study is that the genotypic and/or allelic frequency of MMP-2 rs243865 was differentially distributed among the case and control groups (Table II and Table III). However, none of the CT or TT genotypes at MMP-2 rs243865 or rs2285053 may in combination with age or sex, influence GC susceptibility (data not shown). These findings reporting that MMP-2 rs243865 genotypes may serve as a marker for GC risk prediction are consistent with those of Zhang et al. in China (34), while different from those of Kubben et al. in Netherlands (32), and Alakus et al. in Germany (33). The inconsistency may be due to two possibilities. The first possibility is that different populations were investigated, and the second one is that the influence of MMP-2 on GC risk may be somehow affected by other risk factors, such as personal diet and behaviors. of Both ours and Zhang et al.’s included only Asian populations, while Kubben’s and Alakus’s did not. More investigations in different populations are needed to reach a definite conclusion.

To the best of our knowledge, this is the first epidemiological study based on molecular genetics to evaluate the contribution of MMP-2 rs243865 genotypes and susceptibility to GC in association with cigarette smoking, alcohol drinking, and H. pylori infection status, simultaneously. Interestingly, the CC genotype at MMP-2 rs243865 had additive effects on cigarette smoking and alcohol drinking (Table IV and Table V), and significantly enhanced the influence of H. pylori infection on GC risk (Table VI).

In literature, lots of epidemiological studies have shown that GC risk is higher in cigarette smokers (40–45), while few others have shown a negative association (46, 47). Smyth et al. have reported that smoking was not only a risk factor of GC but associated with a significantly lower 5-year survival rate (48). In the current study, we found that cigarette smoking was associated with GC risk (p=0.0012), especially for heavy smokers (p=0.0001) (Table I). Furthermore, we found that cigarette smoking may interact with MMP-2 rs243865 CC genotypes (OR=4.26, 95%CI=2.09-8.70, p=0.0001) (Table IV).

Furthermore, according to previous findings, the association between alcohol drinking and GC risk remains inconclusive. This is probably due to the different types of alcoholic drinks consumed among different populations. Another explanation is that alcohol metabolism-related genes together with their expression differ among Eastern and Western countries (49, 50). Moreover, people in Taiwan are used to social drinking behaviors without granting themselves as alcohol consumers. IARC concluded that alcoholic beverages are causally related to several types of cancers, including oral cavity, pharyngeal, laryngeal, esophageal, hepatoma, colorectal, and breast cancer (51). However, IARC has not concluded whether alcohol drinking is a risk factor for developing GC (51). In the current study, we found that the percentage of alcohol drinkers among GC patients was higher than that in healthy controls (Table I), and alcohol drinkers had 2.95-fold higher risk of developing GC than non-drinkers (Table V). Furthermore, people carrying the CC genotype at MMP-2 rs243865 and alcohol drinking may have 3.3-fold higher GC risk compared to those not carrying the CC genotype and non-alcohol drinkers (Table V). The identification of alcohol drinking as a risk factor for GC still needs further investigations, and the interaction between alcohol and MMP-2 genotypes remains unresolved.

As for H. pylori infection status, 51.8% of the healthy people in Taiwan were found to be infected, a percentage that is significantly lower than the 70.2% in the 121 GC patients (p=0.0005) (Table I). The stratified analysis showed that among individuals carrying GG/CG genotypes at MMP-2 rs243865, the status of H. pylori infection was non-significant 1.88-fold risk of GC (95%CI=0.74-4.76, p=0.1819) (Table VI). Furthermore, H. pylori infection status would synergistically enhance GC risk in people with the CC genotype at MMP-2 rs243865 (OR=3.85, 95%CI=1.74-8.52, p=0.0005) (Table VI). Our results provide another piece of evidence that although H. pylori infection has been documented as a risk factor of GC, however, only extremely few (1%-2%) H. pylori-infected patients would develop GC (3, 52). The interaction of H. pylori infection with MMP-2 rs243865 genotype on GC risk also requires further investigation.

In conclusion, our findings suggest that the CC genotype of MMP-2 rs243865 was associated with higher risk to GC, and the genotype of MMP-2 combined with cigarette smoking, alcohol drinking, and H. pylori infection, can determine individual susceptibility for GC risk.

Acknowledgements

The Authors are grateful to Yu-Chen Hsiau, Yu-Ting Chin and Tai-Lin Huang for their excellent technical assistance. All the participants in this study are appreciated. This study was supported by Taichung Armed Forces General Hospital to Dr. Fu (grant number: TCAFGH-D-109013) and Asia University and China Medical University Hospital (grand number: CMU110-ASIA-05). The funders had no role in the study design, data collection and analysis, decision to publish or preparation of the manuscript.

Footnotes

  • ↵* These Authors contributed equally to this study.

  • Authors’ Contributions

    Research Design: Fu CK, Mong MC and Bau DT; Questionnaire Summarize: Yang MD; Experiment Performance: Yang YC, Chen JC, Chang WS and Tsai CW; Statistical analysis and confirmation: Pei JS, Hsia NY, Yu CC and Chang WS; Manuscript Writing: Fu CK, Mong MC, Yu CC and Bau DT; Polishing and Correction: Chang WS, Wang ZH and Bau DT.

  • Conflicts of Interest

    All the Authors declare no conflicts of interest in relation to this study.

  • Received January 24, 2022.
  • Revision received February 9, 2022.
  • Accepted February 10, 2022.

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Association of Matrix Metallopeptidase-2 Genotypes With Risk of Gastric Cancer in Taiwan
CHUN-KAI FU, MEI-CHIN MONG, CHIEN-CHIH YU, MEI-DUE YANG, ZHI-HONG WANG, YA-CHEN YANG, JAW-CHYUN CHEN, JEN-SHENG PEI, NING-YI HSIA, CHIA-WEN TSAI, WEN-SHIN CHANG, DA-TIAN BAU
Anticancer Research Apr 2022, 42 (4) 1749-1755; DOI: 10.21873/anticanres.15651
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