Abstract
Background/Aim: Prostate cancer is one of the most commonly diagnosed malignancies among males worldwide. It has been shown that MMP-7 gene is closely correlated with prostate carcinogenesis. However, the role of the MMP-7 genotypes has been seldom examined among prostate cancer patients. Therefore, the purpose of the study was to evaluate the contribution of MMP-7 promoter genotypes A-181G (rs11568818) and C-153T (rs11568819) to prostate cancer risk in Taiwan. Materials and Methods: Two hundred and eighteen prostate cancer patients and 436 sex- and age-matched healthy controls were genotyped for MMP-7 rs11568818 and rs11568819 by polymerase chain reaction-restriction fragment length polymorphism and direct sequencing methodologies. Results: The percentages of wild-type AA, and variant AG and GG genotypes on MMP-7 rs11568818 were 85.3, 13.5, and 1.2% among the prostate cancer cases and 87.6, 10.1, and 2.3% among the healthy controls, respectively (p for trend=0.2557). Interestingly, no MMP-7 rs11568819 genotypes were identified among Taiwanese. The allelic frequency distribution also showed that the variant G allele of MMP-7 rs11568818 seemed not to be a determinant of prostate cancer risk (p=0.7977). There was no joint effect between the genotypes of MMP-7 rs11568818 and age and smoking status on prostate cancer risk. Conclusion: rs11568818 and rs11568819 at MMP-7 promoter region, played no role in determining personal susceptibility to prostate cancer in Taiwan.
Globally, prostate cancer is the second most prevalent cancer, and the fifth leading death-causing cancer among males, with about 1,414,000 newly diagnosed cases and 375,304 deaths in 2020 (1). According to worldwide cancer statistics, prostate cancer is the most frequently diagnosed cancer in one hundred and twelve countries, and the leading death-causing cancer in forty-eight countries (2). In the near future, prostate cancer cases are suggested to increase due to the aging of various populations (3). There are several well-established risk factors for prostate cancer, including aging, black races, and family cancer history (4). At the same time, some lifestyle and dietary factors have been reported to increase the risk of prostate cancer, such as overweight (5), fitness (6), diabetes mellitus (7), risky dietary styles (8), and vitamin E over-supplementation (9). Like for other types of tumors, the goal in prostate cancer is targeted therapy based on patient’s individual susceptibility evaluated using personalized genomics.
The matrix metalloproteinases (MMPs, matrixins) are a group of peptidases that play a critical role in inflammation, carcinogenesis, and cancer cell migration via the regulation of extracellular matrix (ECM) components (10, 11). Several members of MMPs were upregulated in the tissues of various types of cancer, which were highly related to tumor behaviors,, such as invasion (12, 13). Additionally, MMPs can play an important role in metastasis (14, 15). In normal conditions, MMP-7 is constitutively expressed in several types of tissues including parotid glands, liver, pancreas, lung peribronchial glands and most of all, prostate tissues (16). Under physiological conditions, the expression levels of MMP-7 are low; however, it is increased in malignant tissues (17). In recent decades, many studies have reported that single nucleotide polymorphisms (SNPs) on the MMP genes may contribute to individual differences in susceptibility to specific types of cancer, including oral (18-20), esophageal (21), colorectal (22), lung (23, 24), bladder cancer (25), and pterygium (26). Furthermore, the basal activity was higher in promoter constructs of MMP-7 at A-181G (rs11568818) and C-153T (rs11568819) (27). The genotypes of MMP-7 have been investigated for their association with different cancers, including lung, breast, oral, esophageal, gastric, colorectal, gallbladder, bladder cancer, astrocytoma, renal cell carcinoma, and childhood leukemia (28-40), but seldom in prostate cancer (41). In that study, they reported that among 197 prostate cancer cases and 197 healthy controls in Poland, the genotypes of MMP-7 rs11568818 were associated with elevated prostate cancer risk (41).
Therefore, we aimed at evaluating the association of MMP-7 rs11568818 and rs11568819 genotypes with prostate cancer risk in a representative (case:control=436:218) Taiwanese population.
Materials and Methods
Recruited prostate cancer population. The study has been approved by the IRB of the China Medical University Hospital with the code number DMR104-IRB-158. All the clinical questionnaires were recorded according to the principles documented in the Declaration of Helsinki. The healthy controls were matched for age and sex and selected from the Health Examination Cohort of the hospital. The detailed sampling of the cases and controls has been published in our previous papers (42, 43). The selective demographics of all the participants are concisely summarized and compared in Table I.
Demographics of the prostate cancer cases and control subjects.
MMP-7 rs11568818 and rs11568819 genotyping methodology. Genomic DNA was extracted from blood leukocytes as we have previously published (44-46). The MMP-7 genotyping methodology has also been previously published (38). MMP-7 rs11568818 PCR was conducted, and the obtained 150 bp PCR adducts were digested with EcoR I restriction endonuclease (New England BioLabs, Ipswich, MA, USA) and resulted in 120 and 30 bps when the G allele was present. As for MMP-7 rs11568819, direct sequencing PCR was conducted.
Statistical analyzing methodology. The descriptive statistics for the ages of the prostate cancer patients and controls are shown as the mean plus standard deviation (SD). Unpaired Student’s t-test was used to compare the distributions of different ages between the prostate cancer case and control groups. The Pearson’s chi-square or Fisher exact test was used for the evaluation of the associations of MMP-7 genotypes, or the interaction of MMP-7 genotypes with age or smoking status. The potential associations were evaluated as odds ratios (ORs) and 95% confidence intervals (CIs). Adjustment analysis was conducted after adjusting for age or smoking status. Any outcome was considered significant when the p-value was less than 0.05.
Results
Comparison of demographics between the prostate cancer case and control groups. The distributions of demographic characteristics including age, smoking behaviors, and family history for the 436 prostate cancer patients and 218 healthy controls are compared in Table I. First, there was no difference in the distribution of younger (<55-years-old) or elder (355-years-old) age between the prostate cancer patient and control groups since we matched them during the recruiting of healthy controls (p=0.67). Second, smoking behaviors were also similar in prostate cancer patients (81.2%) and control groups (77.0%) (p=0.27). Third, 7.8% and 1.8% of the prostate cancer patients had their first- and second-degree relatives suffering from any type of cancer (Table I).
Association of MMP-7 rs11568818 and rs11568819 genotypes and prostate cancer risk. The genotypic frequency of MMP-7 rs11568818 was not differentially distributed between the control and prostate cancer patient groups (p for trend=0.2557) (Table II, top panel). In detail, the AG or GG at MMP-7 rs11568818 was not associated with significantly altered prostate cancer risk (OR=0.73 and 1.95, 95%CI=0.43-1.22 and 0.56-6.81, p=0.2785 and 0.4679, respectively; Table II). When the homozygotes GG and heterozygotes AG were combined, the results still showed that these genotypes at MMP-7 rs11568818 conferred no risk for prostate cancer (OR=0.82, 95%CI=0.51-1.33, p=0.4971) (Table II). Regarding MMP-7 rs11568819, no polymorphic genotypes except for CC homozygous wild-type was found among the investigated subjects (Table II). It was quite different from the data of the Polish population (41).
Genotypic frequency distributions of matrix metalloproteinase-7 rs11568818 and rs11568819 among the prostate cases and healthy controls.
Association of MMP-7 rs11568818 and rs11568819 allelic frequencies and prostate cancer risk. The results of allelic analysis showed that the variant G allele at MMP-7 rs11568818 was not significantly associated with prostate cancer risk (OR=0.92, 95%CI=0.60-1.43, p=0.7977) (Table III). In detail, the percentages of G allele frequencies were 7.9% and 7.3% in the healthy control and prostate cancer case groups, respectively (Table III). As for MMP-7 rs11568819, all the subjects were C allele carriers in the Taiwanese population (Table III).
Allelic frequencies for matrix metalloproteinase-7 rs11568818 and rs11568819 polymorphisms among the prostate cases and healthy controls.
Joint effects of MMP-7 rs11568818 with age and smoking behavior. Stratification analysis for the MMP-7 rs11568818 genotypes according to age and smoking status was also conducted. No significant association was found regarding these aspects (all p>0.05) (Table IV and Table V). However, the samples in some subgroups, especially those for smoker cases and elder cases, seemed to be limited.
Matrix metalloproteinase-7 rs11568818 genotype in prostate cancer risk after stratification by age.
Matrix metalloproteinase-7 rs11568818 genotype in prostate cancer risk after stratification by smoking status.
Discussion
The incidence of prostate cancer has been increasing in Taiwan since 1979 (47). In the current study, the contribution of MMP-7 genotypes to prostate cancer susceptibility among males in Taiwan was investigated. MMP-7 regulates ECM contents in various organs and tissues (48); therefore, it is reasonable to hypothesize that genetic variations in this gene may determine personal susceptibility to inflammatory responses and tumorigenesis (49).
One of the highlights of this study is that the G allele of MMP-7 rs11568818 does not contribute to personal prostate cancer susceptibility (Table II and Table III). To the best of our knowledge, the current study is the first to reveal the contribution of MMP-7 promoter genotypes to prostate cancer in Taiwan. Our results contradict those of a study conducted in the Polish population (41). The comparison of the two studies indicates that our samples are more genetically conserved (all Taiwanese) and representative (case: control=197:197 versus 218:436, respectively). The controls were matched by age and smoking status with the cases in both studies. However, the patterns of genotypic distributions were quite different between the two studies. In Bialkowska’s study, the genotypic percentages of MMP-7 rs11568818 AA, AG, and GG were 38.6%, 49.2% and 12.2%, respectively (41), whereas in our study, the genotypic percentages of MMP-7 rs11568818 AA, AG, and GG were 85.3%, 13.5% and 1.2%, respectively (Table II). The dramatic differences in genotypic patterns are largely due to different genetic backgrounds. Therefore, the MMP-7 rs11568818 is a specific marker for prostate cancer in Poland, but not in Taiwan. Supporting evidence may come from the following studies. First, the MMP-7 rs11568818 G allele may facilitate the binding affinity of nuclear activating proteins in the promoter region of MMP-7, causing a higher transcriptional activity than that of A allele (27). In 2001, MMP-7 was found to be upregulated during sex hormone-induced prostate carcinogenesis (50). In 2013, MMP-7 gene was reported to be up-regulated in LNCaP prostate cancer cells (51). In 2014, MMP-7 maturation was reported to play a critical role in prostate cancer cell behavior (52). The discrepancies between the two studies can be explained by population specificity. For instance, Eeles et al. examined 40,000 European individuals, reporting an association of MMP-7 rs11568818 genotypes with prostate cancer risk (53). Hoffmann et al. investigated 34,000 non-Hispanic white individuals, also reporting an association of MMP-7 rs11568818 genotypes with prostate cancer risk (54). The lack of association in our study needs further validations among Asia populations.
In conclusion, this study examined the genotypic patterns of MMP-7 among Taiwanese and revealed that neither MMP-7 rs11568818 nor rs11568819 contributed to personal susceptibility to prostate cancer. Further validations among Asia populations are needed to validate population specificity.
Acknowledgements
The Authors appreciate the Tissuebank of China Medical University Hospital for their excellent help in sample collection. This study was supported with grants from Taichung Armed Forces General Hospital (TCAFGH-D-111024) and China Medical University and Asia University (CMU111-ASIA-06).
Footnotes
Authors’ Contributions
Research design: Liao CH, Chang WS and Hsu WL; patient and questionnaire summaries: Liao CH, Wu HC and Chen CH; experimental work: Chang WS, Hu PS and Hsu SW; statistical analysis: Hsia TC, Yueh TC and Wang BR; article writing: Chang WS and Tsai CW; review and revision: Huang WC and Bau DT.
Conflicts of Interest
The Authors declare no conflicts of interest in relation to this study.
- Received July 8, 2022.
- Revision received July 25, 2022.
- Accepted July 26, 2022.
- Copyright © 2023 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.
