Abstract
Background/Aim: Gastric cancer (GACA) is a major global health burden, ranking fifth in incidence and third in cancer-related mortality worldwide. Despite growing knowledge of environmental risk factors such as Helicobacter pylori infection, smoking, and alcohol consumption, the role of genetic susceptibility, particularly polymorphisms in matrix metalloproteinase-11 (MMP-11), in GACA pathogenesis remains unclear.
Materials and Methods: We conducted a hospital-based case-control study involving 161 patients with GACA and 483 age- and sex-matched cancer-free controls of Taiwanese ethnicity. Four MMP-11 single nucleotide polymorphisms (SNPs), rs738791, rs2267029, rs738792, and rs28382575, were genotyped using PCR-RFLP and direct sequencing. Logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with a significance threshold of p<0.05.
Results: Overall, no significant associations were observed between MMP-11 SNPs and GACA susceptibility. However, the rs28382575 C allele was associated with increased risk (p=0.0377). Stratified analysis revealed that rs738791 CT/TT genotypes were significantly associated with metastasis (p=0.0129). Among smokers and drinkers, rs28382575 CT/CC genotypes conferred elevated risk (smokers: p=0.0027; drinkers: p=0.0153), while rs738792 variant genotypes appeared protective (smokers: p=0.0124; drinkers: p=0.0022).
Conclusion: While MMP-11 polymorphisms are not suitable as population-level screening markers for GACA risk, rs738791 and rs28382575 may serve as predictors for metastasis, and rs28382575 and rs738792 as modifiers of gene-environment interaction. Functional validation is warranted to elucidate the biological relevance of these findings in GACA progression.
- Alcohol drinking
- gastric cancer
- genotypes
- matrix metalloproteinase-11
- metastasis
- single nucleotide polymorphism
- smoking
Introduction
Gastric cancer (GACA) ranks as the fifth most commonly diagnosed malignancy and the third leading cause of cancer-related mortality worldwide (1). In 2022, approximately 968,000 new cases and 660,000 deaths were attributed to this disease globally (2). Despite substantial progress in diagnostic and therapeutic strategies, GACA continues to pose a major global health challenge owing to its intricate molecular pathogenesis, dismal prognosis, and the paucity of robust predictive biomarkers (3). From the epidemiological viewpoint, a range of environmental and lifestyle factors have been implicated in gastric carcinogenesis, including Helicobacter pylori (H. pylori) infection (4, 5), cigarette smoking (6, 7), alcohol drinking (8, 9), obesity (10, 11), and diet (12, 13). Furthermore, growing evidence indicates that the interplay between environmental exposures and host genetic susceptibility constitutes a pivotal, yet incompletely elucidated, determinant in the multifactorial etiology of GACA (14, 15). Nevertheless, the discovery and validation of genetic markers that could facilitate early detection or accurately predict individual susceptibility to GACA remain insufficiently explored.
Matrix metalloproteinase-11 (MMP-11), also referred to as stromelysin-3 or matrix decomposin-3 (ST-3), is encoded by the MMP-11 gene located on human chromosome 22q11.23 (16). The expression levels of MMP-11 could be used to identify patients at greater risk for cancer recurrence in breast carcinoma (17), pancreatic tumors (18), and colorectal cancer (19). Dysregulated over-expression of MMP-11 has been reported across a broad spectrum of malignancies, including poorly differentiated high-grade thyroid (20), breast (21, 22), lung (23), oral (24, 25), esophagus (26), colorectum (27-29), pancreas (30), and ovary (31). Despite extensive evidence implicating MMP-11 in tumorigenesis and cancer progression, its expression pattern and biological relevance in GACA remain insufficiently characterized. Given MMP-11’s established roles in extracellular matrix remodeling, tumor invasion, and metastasis, elucidating the genetic variations of MMP-11 and their potential association with GACA susceptibility could provide valuable insights into its pathogenic mechanisms and identify novel predictive biomarkers for disease risk and progression. This finding suggests that MMP-11 may provide enhanced clinical utility as a biomarker for GACA detection. In a pilot investigation, MMP-11 exhibited superior diagnostic sensitivity for GACA compared with several conventional tumor markers, including carcinoembryonic antigen (CEA), cancer antigen (CA) 19-9, CA-242, and MMP-9 (32). While CEA is broadly used as a general malignancy marker, CA19-9 and CA-242 are primarily applied in the assessment of gastrointestinal and pancreatic cancers. In another study, a certain cut-off value of MMP-11 protein could reach 94.0% sensitivity and 93.7% specificity for diagnosis of gastric adenocarcinoma (33).
A growing body of molecular epidemiological evidence has explored the associations between MMP-11 polymorphisms and the risk of diverse human malignancies (34-37). Despite these advances, no study to date has specifically examined the influence of MMP-11 genetic variants on GACA susceptibility. To fill this knowledge gap, we performed a hospital-based case-control study to investigate the potential contribution of four MMP-11 single nucleotide polymorphisms (SNPs), rs738791, rs2267029, rs738792, and rs28382575 (Figure 1), to GACA risk in a Taiwanese population. The study cohort consisted of 161 patients with histologically confirmed GACA and 483 cancer-free controls matched for age and sex.
Physical maps for the sequences nearby MMP-11 rs738791, rs2267029, rs738792, and rs28382575 polymorphic sites.
Materials and Methods
Recruitment of hospital-based GACA and matched control cohort. This hospital-based case-control study was designed to investigate the association between MMP-11 polymorphisms and susceptibility to GACA. A comprehensive description of the study population has been reported previously (38-40), and a concise summary is presented in Table I. In total, 161 patients with histologically confirmed GACA were recruited from the Department of General Surgery, China Medical University Hospital (CMUH), a major tertiary medical center in central Taiwan. Detailed clinicopathological information for each patient was systematically documented at the time of enrollment. Control subjects were recruited from the same hospital during routine health examinations and were individually matched to cases at a 3:1 ratio according to age and sex. All participants, both cases and controls, were ethnically Taiwanese. The study protocol was reviewed and approved by the Institutional Review Board of China Medical University Hospital (DMR100-IRB-107) and was conducted in accordance with the ethical principles of the Declaration of Helsinki. Written informed consent was obtained from all participants prior to sample collection.
Selected characteristics of the control and gastric cancer groups.
Procedure for MMP-11 genotyping. Genomic DNA was extracted from peripheral blood leukocytes obtained from both patients with GACA and healthy controls using a commercial DNA extraction kit (Blossom, Taipei, Taiwan, ROC), following standardized molecular protocols as previously described (41, 42). The genotyping of MMP-11 polymorphisms, including rs738791, rs2267029, rs738792, and rs28382575, was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis for rs2267029 and rs738792, and direct sequencing for rs738791 and rs28382575, according to previously established methods (43, 44).
Statistical analysis of MMP-11 polymorphisms in GACA. The genotypic distributions of individual MMP-11 variants in both GACA patients and control subjects were assessed for conformity with Hardy-Weinberg equilibrium (HWE) using the chi-square goodness-of-fit test. Differences in mean age between the two groups were evaluated using the unpaired Student’s t-test. Categorical variables, including smoking status, alcohol consumption, body mass index (BMI), H. pylori infection, MMP-11 genotypes, and allelic frequencies, were compared using Pearson’s chi-square test. The associations between MMP-11 polymorphisms and the risk of developing GACA were estimated by calculating odds ratios (ORs) and corresponding 95% confidence intervals (CIs) using unconditional logistic regression models. All statistical analyses were performed with a predefined significance threshold of p<0.05.
Results
Distribution of MMP-11 polymorphisms and their association with GACA risk. The distribution profiles of four MMP-11 SNPs were examined among 161 patients with GACA and 483 cancer-free controls, as summarized in Table II. The genotypic frequencies of all four SNPs in the control group conformed to HWE (p=0.1972, 0.2355, 0.1771, and 0.1222, respectively), indicating population representativeness. No statistically significant associations were observed between GACA susceptibility and any of the examined MMP-11 polymorphisms under either the co-dominant or dominant genetic models (Table II), with the exception of rs28382575, which demonstrated a borderline association (OR=1.82, 95%CI=1.02-3.25, p=0.0612). Consistent with these findings, allelic distribution analysis (Table III) mirrored the genotypic trends. Notably, the variant C allele at rs28382575 was significantly associated with an elevated risk of GACA compared with the wild-type T allele (OR=1.84, 95%CI=1.07-3.17, p=0.0377).
Genotypic frequency distributions of matrix metalloproteinase-11 genotypes among the GACA cases and healthy control subjects.
Allelic frequencies for matrix metalloproteinase-11 polymorphisms among the GACA cases and healthy subjects.
Association of MMP-11 genotypes with clinicopathological features of GACA. The potential influence of the four MMP-11 polymorphic genotypes on the clinicopathological characteristics of GACA patients was further assessed, and the detailed results are presented in Table IV, Table V, Table VI, and Table VII. Among these variants, carriers of the CT or TT genotypes at rs738791 demonstrated a significant association with the presence of metastasis (p=0.0129; Table IV). Moreover, the CT or TT genotypes at rs738792 appeared to have a protective effect among GACA patients who had cigarette smoking and alcohol drinking habits (p =0.0124 and 0.0022, respectively; Table VI). Conversely, individuals harboring the CT or CC genotypes of rs28382575 exhibited a significantly higher risk of GACA in the subgroups of smokers and alcohol drinkers (p =0.0027 and 0.0153, respectively; Table VII). In addition, the association between the rs28382575 CT or CC genotypes and metastatic status in patients with GACA approached statistical significance (p=0.0606; Table VII).
Combinative effects of matrix metalloproteinase-11 rs738791 genotype with demographic and clinical features on gastric cancer risk.
Combinative effects of matrix metalloproteinase-11 rs2267029 genotype with demographic and clinical features on gastric cancer risk.
Combinative effects of matrix metalloproteinase-11 rs738792 genotype with demographic and clinical features on gastric cancer risk.
Combinative effects of matrix metalloproteinase-11 rs28382575 genotype with demographic and clinical features on gastric cancer risk.
Discussion
In 2013, Gencer and his colleagues investigated the relationship between MMP expression and oxidative stress in two GACA cell lines, MKN-45 and 23132/87 (45). Their findings revealed that the expression levels of several MMPs, including MMP-1, MMP-7, MMP-14, MMP-15, and MMP-17, were up-regulated under oxidative stress conditions. However, the authors acknowledged that other MMPs, such as MMP-11, might also be activated through alternative regulatory mechanisms not directly examined in their study. Subsequently, in 2014, Chang and his colleagues reported that elevated serum levels of MMP-3, MMP-7, and MMP-11, along with increased intratumoral expression of MMP-9, MMP-12, and MMP-21, were significantly associated with poor overall survival in patients with GACA (46). However, the specific molecular mechanisms underlying these associations and the particular GACA subtypes affected remain largely uncharacterized. Building upon these findings, Su and his colleagues in 2018 provided mechanistic insights at the cellular level, demonstrating that MMP-11 expression can be up-regulated by insulin-like growth factor-1 (IGF-1), thereby enhancing the proliferative and invasive capabilities of GACA cells via activation of the JAK1/STAT3 signaling pathway (47). Further supporting the clinical relevance of MMP-11, a study by Yan and his colleagues found that patients with low MMP-11 expression exhibited significantly longer median survival times and higher one-year survival rates compared to those with high MMP-11 expression (33). In the present study, we evaluated the association between four MMP-11 polymorphisms (rs738791, rs2267029, rs738792, and rs28382575) and susceptibility to GACA. Our genotypic analysis revealed that none of the examined variants was statistically significantly associated with GACA risk (Table II). Similarly, allele frequency distributions did not support a predictive role for these polymorphisms as genetic biomarkers of GACA susceptibility (Table III). Notably, none of these four SNPs are located within the promoter region of MMP-11, and therefore are unlikely to directly modulate transcriptional activity through cis-regulatory mechanisms.
To provide a comprehensive and systematic evaluation, we analyzed the distribution of rs738791, rs2267029, rs738792, and rs28382575 in relation to various clinicopathological features in patients with GACA. Among these, the rs738791 polymorphism, an intronic variant, exhibited a statistically significant association with metastatic disease. Specifically, individuals harboring the CT or TT genotypes showed a higher likelihood of presenting with metastasis compared to those with the CC genotype (p=0.0129; Table IV). This observation is particularly relevant given that approximately 70% of patients with GACA are diagnosed at an advanced or metastatic stage, which typically precludes curative surgical intervention and is associated with poor prognosis (48). Previous studies have confirmed endogenous expression of MMP-11 in GACA cells using western blotting and immunohistochemical staining (49). Notably, MMP-11 expression is significantly elevated in GACA tissues compared to nonmalignant gastric tissues at both the transcript and protein levels (50). Consistent with tissue findings, serum levels of MMP-11 are also significantly higher in patients with advanced GACA relative to healthy controls (33). These data collectively underscore the potential clinical importance of rs738791. It is now critical to determine whether carriers of the rs738791 T allele exhibit elevated MMP-11 expression, which may mechanistically contribute to enhanced metastatic potential in GACA. If confirmed, this polymorphism could serve as a predictive biomarker for aggressive disease. In future clinical practice, patients carrying the CT or TT genotypes at rs738791 may warrant more intensive systemic surveillance to facilitate early detection of metastasis and improve disease management.
Alcohol consumption and cigarette smoking are well-recognized environmental risk factors contributing to the development of GACA (6, 51). Despite their established roles, the interplay between environmental exposures and genetic susceptibility remains poorly explored in the context of GACA. Understanding such gene-environment interactions is essential to fully elucidate the disease’s etiology. Among the MMP-11 polymorphisms examined, rs738792 is the only missense variant, resulting in a non-synonymous substitution of alanine (C allele) to valine (T allele) (52). This amino acid change has the potential to alter the structure or functional properties of the MMP-11 protein. Notably, our stratified analysis revealed that carriers of the variant genotypes at rs738792 demonstrated a reduced risk of GACA among individuals with a history of cigarette smoking or alcohol consumption (Table IV), suggesting a possible protective role under specific environmental conditions. In contrast, the variant genotypes of rs28382575 were significantly associated with an increased risk of GACA in the same subgroups of smokers and drinkers (Table VII). These contrasting patterns highlight the complexity of gene-environment interactions and suggest that MMP-11 may contribute to gastric carcinogenesis through mechanisms beyond its classical role in extracellular matrix degradation. It is plausible that MMP-11 participates in other regulatory networks or signaling cascades that remain to be identified. Importantly, these novel findings have not been previously reported in the literature. Elucidation of the underlying molecular mechanisms will require experimental validation in appropriate GACA cellular models, as such insights cannot be obtained solely through epidemiological or association studies. Further investigation at the functional level is therefore essential to clarify the biological significance of these polymorphisms in the context of gene-environment interactions.
In summary, this study demonstrates that none of the examined MMP-11 polymorphic sites, including rs738791, rs2267029, rs738792, and rs28382575, appears to serve as reliable standalone biomarkers for population-level screening of GACA susceptibility. However, our findings suggest that specific variants may hold prognostic or predictive value in certain clinical contexts. Notably, rs738791 and rs28382575 were associated with metastatic disease, while rs28382575 and rs738792 were linked to differential GACA risk among individuals with environmental exposures such as smoking and alcohol consumption. These results underscore the importance of investigating the functional consequences of MMP-11 polymorphisms, particularly in the context of gene-environment interactions. Future research should aim to elucidate how these variants influence MMP-11 expression, protein function, and downstream signaling pathways. Additionally, reevaluating the role of MMP-11 in extracellular matrix remodeling and its potential involvement in alternative regulatory networks may yield novel insights into GACA pathogenesis. Overall, while MMP-11 polymorphisms may not be suitable for primary screening, they could contribute to individualized risk stratification, prognosis, and potentially inform therapeutic strategies. The continued investigation of MMP-11’s role in GACA progression remains a critical avenue for advancing our understanding of this malignancy and improving patient outcomes.
Acknowledgements
The Authors would like to acknowledge the Tissue-Bank of China Medical University Hospital for their invaluable data collection. In addition, the technical supports from Yun-Chi Wang and Ai-Chia Tung is highly appreciated. Furthermore, the authors would like to extend their gratitude to all the study participants, as well as the doctors, nurses, and colleagues who contributed to the study. This study is supported by the grants from China Medical University and Asia University (CMU113-ASIA-02) and Taichung Armed Forces General Hospital (TCAFGH-D-114024).
Footnotes
Authors’ Contributions
Conceptualization: Fu CK, Tsai CW, Mong MC and Chang WS; Collection: Fu CK, Lee HT, Yang MD, and Yueh TC; Data curation: Fu CK, Mong MC, Lee HT, Yang MD, and Yueh TC; Genotyping: Tsai CW, Chen JC, Hsu CL, and Chang WS; Statistics: Lee HT, Chen JC, Chang WS and Tsai CW; Project administration: Fu CK, Chang WS, and Bau DT; Supervision: Bau DT, Tsai CW and Chang WS; Validation: Hsia TC, and Bau DT; Writing – original draft: Fu CK, Tsai CW, Bau DT, and Chang WS; Writing – review and editing: Bau DT and Chang WS. All Authors have read and agreed to the published version of the manuscript.
Conflicts of Interest
The Authors declare no conflicts of interest regarding this study.
Artificial Intelligence (AI) Disclosure
No artificial intelligence tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received October 13, 2025.
- Revision received October 25, 2025.
- Accepted October 27, 2025.
- Copyright © 2026 The Author(s). Published by the International Institute of Anticancer Research.
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