{"paper_id":"9698c6af-e946-498e-b0b4-eb536483da53","body_text":"Abstract. Background/Aim: The activity and expression of \nmatrix metalloproteinase-7 (MMP7) have been found to be \nupregulated in the late stages of endometriosis. However, the \ncontribution of MMP7 genotype to endometriosis has seldom \nbeen examined. This study aimed to investigate the role of \nMMP7 promoter A-181G (rs11568818) and C-153T \n(rs11568819) genotypes in determining personal susceptibility \nto endometriosis in a Taiwanese cohort. Patients and Methods: \nIn this hospital-based case–control study, MMP7 genotypes \nwere analyzed in 153 endometriosis and 636 individuals \nwithout endometriosis using typical polymerase chain reaction-\nrestriction fragment length polymorphism methodology. \nResults: The statistical analysis revealed that MMP7 \nrs11568818 genotypes were differentially distributed between \nthe endometriosis and control groups (p for trend=0.0048). \nSpecifically, the MMP7 rs11568818 homozygous variant GG \nwas associated with endometriosis risk compared to the wild-\ntype AA genotype (OR=4.59, 95% CI=1.46-14.48, p=0.0136). \nHowever, the MMP7 rs11568818 heterozygous variant AG was \nnot associated with endometriosis risk (OR=1.57, 95% \nCI=0.97-2.53, p=0.0854). The frequency of than variant allele \nG of MMP7 rs11568818 was 12.7% in the endometriosis \ngroup, significantly higher than the 7.2% observed in the \ncontrol group (OR=1.90, 95% CI=1.27-2.82, p=0.0021). \nConclusion: MMP7 rs11568818 GG genotype was found to be \na novel marker for endometriosis risk in Taiwanese. \n \nEndometriosis is a hormone-dependent, inflammatory, benign \ngynecological disease characterized by the growth of \nendometrial cells outside the uterus (1, 2). It is a significant \nhealth concern affecting approximately 10% of women of \nreproductive age globally (3). In Taiwan, the prevalence of \nendometriosis has been observed to have increased in recent \nyears, with estimated rates ranging from 1.5% to 30.8% among \nwomen of reproductive age (4-6). Women with endometriosis \nhave an elevated risk of developing ovarian, breast, endocrine, \nand colorectal cancer (7, 8). Clinical features include \ndysmenorrhea, chronic pelvic pain, painful intercourse, and \ninfertility (2). Although the etiology of endometriosis remains \nincompletely understood, accumulating evidence suggests that \nit is a multifactorial disease involving inflammation, hormonal \ndysregulation, and genetic factors (9-11). \nThe matrix metalloproteinases (MMPs) are a group of \npeptidases that play a critical role in inflammation, \ncarcinogenesis, and cancer cell migration through the regulation \nof extracellular matrix (ECM) components (12, 13). MMP7 is \nnormally expressed in bronchial, ductal, skin glandular, \n3051\n*These Authors contributed equally to this study. \n \nCorrespondence to: Da-Tian Bau, Terry Fox Cancer Research \nLaboratory, China Medical University Hospital, 2 Yuh-Der Road, \nTaichung, 404 Taiwan, R.O.C. Tel.: +886 422053366 Ext. 5805, e-\nmail: 013280@tool.caaumed.org.tw; Chia-Wen Tsai, Terry Fox \nCancer Research Laboratory, China Medical University Hospital, 2 \nYuh-Der Road, Taichung, 404 Taiwan, R.O.C. Tel.: +886 \n422053366 Ext. 5805, e-mail: 017891@tool.caaumed.org.tw \n \nKey Words: Endometriosis, genotype, MMP7, polymorphism, Taiwan. \nANTICANCER RESEARCH 44: 3051-3058 (2024) \ndoi:10.21873/anticanres.17118\nContribution of Matrix Metalloproteinase-7 \nGenotypes to Endometriosis Risk in Taiwan \n \nHUNG-JU CHIEN 1,2, YUN-CHI WANG3,4, WEN-SHIN CHANG 3,4, YI-HSIEN HSIEH 1, \nYEN-FANG LIU5, YA-CHEN YANG6, JAW-CHYUN CHEN7, DA-TIAN BAU 3,4,8* and CHIA-WEN TSAI 3,4* \n \n1Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C.; \n2Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.; \n3Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.; \n4Terry Fox Cancer Research Laboratory, Department of Medical Research, \nChina Medical University Hospital, Taichung, Taiwan, R.O.C.; \n5Department of Nursing, China Medical University Hospital, Taichung, Taiwan, R.O.C.; \n6Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan, R.O.C.; \n7Department of Medicinal Botanicals and Foods on Health Applications, \nDa-Yeh University, Changhua, Taiwan, R.O.C.; \n8Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C.\nThis article is an open access article distributed under the terms and \nconditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 \ninternational license (https://creativecommons.org/licenses/by-nc-nd/4.0).\n\n\nurogenital, gastrointestinal, and especially endometrial tissues \n(14). Conversely, low levels of MMP7 expression are reported \nin lung, gallbladder, and bladder tissues, and normally ultra-low \nlevels of MMP7 are upregulated in abnormal conditions, such \nas malignant tumorigenesis (15-17). As evidenced by the \nliterature, MMP7 is responsible for cleaving a variety of ECM \nproteins, including collagen IV , fibronectin, laminin, and \ntenascin-C, as well as non-ECM proteins, such as E-cadherin, \ntumor necrosis factor-α, and other MMP family members (14, \n18-22). Thus, MMP7 plays a crucial role in maintaining the \nbalance of many cellular processes, including cell growth, \ninflammation, wound healing, cell remodeling, carcinogenesis, \nand angiogenesis (23-27). Moreover, MMP7 is specifically \nexpressed in multiple tumor types, such as digestive (28), \nurinary (29, 30), and reproductive (31) system tumors. By \ninhibiting apoptosis of cancer cells (32), reducing cell adhesion \n(33), and inducing angiogenesis (34), MMP7 promotes tumor \nprogression and functions as an oncogenic protein that regulates \nthe occurrence and development of various tumors. \nAmong these MMPs, the gene for MMP7 is located on \nhuman chromosome 11 q22.3 and consists of 13 exons (35). \nIn terms of the genotype–phenotype correlation, increased \nMMP7 activity was observed in promoter constructs containing \nthe MMP7 rs11568818 and rs11568819 variant alleles (36). \nPrevious literature has examined the association of MMP7 \ngenotypes with various cancer types, such as oral, esophageal, \ngastric, colorectal, gallbladder, lung, breast, bladder and \nprostate, astrocytoma, renal cell carcinoma, and childhood \nleukemia (37-43). However, the investigation of MMP7 \ngenotypes in relation to endometriosis is extremely limited. At \nthe time of writing, there were only four reports (44-47). \nBased on the aforementioned information, our study aimed \nto assess the potential correlation between MMP7 rs11568818 \nand rs11568819 genotypes and the risk of developing \nendometriosis in a Taiwanese cohort consisting of 153 patients \nwith endometriosis and 636 healthy controls. The selected \nMMP7 polymorphic sites are illustrated in Figure 1. \n \nPatients and Methods \n \nRecruitment of patients with endometriosis and non-endometriosis \ncontrol groups. One hundred and fifty-three individuals diagnosed \nwith endometriosis were enrolled at China Medical University \nHospital between 2000 and 2010. The doctors confirmed the \ndiagnosis of endometriosis and classified the cases according to the \nguidelines established by the American Society for Reproductive \nMedicine (48). Participants were excluded if they had leiomyoma, \nadenomyosis, or any uterine, cervical, or ovarian cancer, and if they \nhad received hormone therapy within the preceding 12 months. The \nbasal follicle-stimulating hormone level was 7.2±1.4 IU/l. All patients \nprovided written informed consent and donated 5 mL of peripheral \nblood for DNA extraction and genotyping analyses. Additionally, 636 \nhealthy individuals without endometriosis were recruited as controls. \nTo minimize the likelihood of including individuals with \nendometriosis in the control group, potential controls who reported \nany symptoms (such as pelvic pain) or had suspicion of endometriosis \nduring our questionnaire interview were recommended for pelvic \nexams, ultrasound, or magnetic resonance imaging and excluded from \nthe control group. However, we acknowledge that some controls may \nstill have had undiagnosed endometriosis, as up to 16-20% of patients \nwith endometriosis may be asymptomatic (4-6). Regarding the \nquestionnaire, we collected and kept confidential information about \nparticipants’ personal smoking and drinking habits, age of menarche, \nand pregnancy history. We defined smokers as individuals who had \nsmoked at least five packs of cigarettes in their lifetime and reported \nsmoking on a daily or almost daily basis. Smokers were also asked \nabout the age at which they began smoking, whether they continued \nsmoking or had quit, and if so, when they quit. Furthermore, they \nwere asked to report their average daily cigarette consumption. Non-\ndrinkers were classified as individuals who consumed less than 200 \nmL of alcohol per week and consumed alcohol less than twice per \nmonth for social purposes. \n \nMMP7 genotyping methodology. The DNA extraction procedure \nutilized in this study involved the use of the QIAamp Blood Mini \nKit (Blossom, Taipei, Taiwan, ROC) to extract peripheral blood \nleukocytes from each participant, as described in prior publications \n(49, 50). The primer design, selection of corresponding restriction \nendonucleases, and polymerase chain reaction conditions for \ngenotyping of MMP7 were consistent with those employed in our \nprevious publication (51). The genotyping procedure was conducted \nindependently and in a double-blind manner by at least two well-\ntrained researchers, with each genotypic analysis being repeated \nmultiple times. The results of all repeated genotyping analyses were \nfound to be 100% concordant with one another. \n \nStatistical analyses. Age indices between the endometriosis case and \ncontrol groups were compared using Student’s t-test. Distribution \nof the MMP7 genotypes among analyzed subgroups was assessed \nusing Pearson’s chi-square test. The contribution of MMP7 \ngenotypes to endometriosis risk was evaluated using odds ratios \n(ORs) and their associated 95% confidence intervals (CIs). \nStatistical significance was defined as a p-value of less than 0.05. \n \nResults \n \nDemographic characteristics of the investigated population. \nTable I presents the frequency distributions of age, age at \nmenarche, full-term pregnancy, smoking and alcohol \nconsumption status, and clinical stages of endometriosis in \n153 patients with endometriosis and 636 healthy controls \nwithout endometriosis. The cases had a mean age of \n40.3±4.9 years, and 55 (35.9%) of them had not experienced \na full-term pregnancy. Among the patients, 32 (20.9%) had \nminimal or mild endometriosis (stage I or II), while 121 \n(79.1%) had moderate or severe endometriosis (stage III or \nIV) according to the revised American Fertility Society \nclassification (48). No significant difference was observed in \nage at menarche and smoking and alcohol consumption \nstatus between cases and controls ( p>0.05). However, the \npercentage of full-term pregnancies was significantly lower \n(p=0.0041) among patients with endometriosis (64.1%) than \namong women without endometriosis (75.9%) (Table I). \nANTICANCER RESEARCH 44: 3051-3058 (2024)\n3052\n\nMMP7 genotyping outcomes. Table II presents the distribution \nof MMP7 rs11568818 and rs11568819 genotypes among 153 \nendometriosis cases and 636 healthy controls. The results \nrevealed that the MMP7 rs11568818 genotypes were \ndifferentially distributed between the endometriosis and control \ngroups (p for trend=0.0048) (Table II). Specifically, the MMP7 \nrs11568818 homozygous GG variant was found to be associated \nwith an increased risk of endometriosis compared to the wild-\ntype AA genotype (OR=4.59, 95% CI=1.46-14.48, p=0.0136, \nTable II). However, the MMP7 rs11568819 heterozygous AG \nvariant was not associated with endometriosis risk (OR=1.57, \n95% CI=0.97-2.53, p=0.0854, Table II). In the dominant model, \nthe data demonstrated that the frequency of MMP7 rs11568818 \nG allele-bearing genotypes was significantly higher in the \nendometriosis group than in the healthy control group (21.6% \nversus 13.4%, respectively; OR=1.78, 95% CI=1.14-2.79, \nChien et al: MMP7 Genotype in Endometriosis\n3053\nFigure 1. The polymorphic sites of matrix metalloproteinase-7 (MMP7) rs11568818 and rs11568819 on chromosome 11.\nTable I. Demographics of the 153 endometriosis and 636 healthy controls. \n \nCharacteristic Cases (n=153) Controls (n=636) p-Value \n \n N % N % \n \nAge (mean±SD) 40.3±4.9 41.2±4.5 0.8865 \nAge at menarche \n ≥12.8 Years 85 55.6% 318 50.0% 0.2418 \n >12.8 Years 68 44.4% 318 50.0% \nFull-term pregnancy \n No 55 35.9% 153 24.1% 0.0041 \n Yes 98 64.1% 483 75.9% \nSmoking status \n Non-smokers 113 73.9% 476 74.8% 0.8361 \n Smokers 40 26.1% 160 25.2% \nAlcohol drinking status \n Non-drinkers 116 75.8% 463 72.8% 0.4772 \n Drinkers 37 24.2% 173 27.2% \nStage \n I or II 32 20.9% \n III or IV 121 79.1% \n \nStatistical analysis was based on Pearson’s chi-square with Yates’ correction test. Statistically significant p-values are shown in bold. \n\np=0.0001, Table II). It is worth noting that all individuals had \nthe CC genotype at the rs11568819 polymorphic site, without \nany CT or TT genotype carriers (Table II). \n \nMMP7 allelic frequency distribution. Consistent with the \nresults in Table II, the frequency of the MMP7 rs11568818 \nvariant allele G was 12.7% in the endometriosis group, \nwhich was significantly higher than the 7.2% observed in the \ncontrol group (OR=1.90, 95% CI=1.27-2.82, p=0.0021, \nTable III). Furthermore, the allelic frequency of MMP7 \nrs11568819 was 100% for the C allele in both the case and \ncontrol groups (Table III). \n \nDiscussion \n \nMMP7 was initially reported to be expressed primarily in \nepithelial endometrial cells in 1993 (52). Subsequently, \naccumulating evidence has demonstrated that the levels of \nvarious MMPs, such as MMP2 and MMP9, are increased in \nthe ectopic tissues and peritoneal fluids of patients with \nendometriosis (53). Nevertheless, only a limited number of \nstudies have investigated the involvement of MMP7 in the \npathogenesis of endometriosis, and its genetic contribution \nhas not yet to be thoroughly examined (54). \nIn this case–control study, we investigated MMP7 genotype \nprofiles in a representative Taiwanese population of 789 \nindividuals, comprising 153 endometriosis cases and 636 non-\nendometriosis controls (as shown in Table I). Our study is the \nfirst to evaluate the contribution of MMP7 genotypes to \nendometriosis risk among Taiwanese. One of the significant \nfindings is that MMP7 rs11568818 genotypes were \ndifferentially distributed between the endometriosis and \ncontrol groups (as presented in Table II), suggesting that the \nGG and AG genotypes of MMP7 rs11568818 could potentially \nserve as novel diagnostic predictors for endometriosis. \nNotably, the G allele of MMP7 rs11568818 has been identified \nas an effective biomarker for endometriosis worldwide. In \n2006, Shan and colleagues reported that variant (GG and AG) \ngenotypes of MMP7 rs11568818 were a risk factor for \nendometriosis in a Chinese population containing 160 controls \nANTICANCER RESEARCH 44: 3051-3058 (2024)\n3054\nTable II. Genotypic frequency distributions of matrix metalloproteinase-7 rs11568818 and rs11568819 among the 153 endometriosis cases and 636 \nhealthy controls. \n \nGenotype Controls, n (%) Cases, n (%) OR (95%CI) p-Valuea \n \nrs11568818 \n AA 551 (86.6) 120 (78.4) 1.00 (Reference) \n AG 79 (12.4) 27 (17.7) 1.57 (0.97-2.53) 0.0854 \n GG 6 (1.0) 6 (3.9) 4.59 (1.46-14.48) 0.0136 \n AG+GG 85 (13.4) 33 (21.6) 1.78 (1.14-2.79) 0.0001 \n ptrend 0.0048 \n pHWE 0.1013 \nrs11568819 \n CC 636 (100.0) 153 (100.0) 1.00 (Reference) -- \n CT 0 (0.0) 0 (0.0) -- \n TT 0 (0.0) 0 (0.0) -- \npHWE 1.0000 \n \nCI: Confidence interval; OR: odds ratio. aChi-square test with Yates’ correction; ptrend: p-value based on trend analysis; pHWE: p-value based on \nHardy–Weinberg equilibrium. Statistically significant p-values are shown in bold. \nTable III. Allelic frequencies for matrix metalloproteinase-7 rs11568818 and rs11568819 polymorphisms among the endometriosis cases and h ealthy \ncontrols. \n \nGenotype Controls, n (%) Cases, n (%) OR (95%CI) p-Valuea \n \nrs11568818 \n Allele A 1181 (92.8) 267 (87.3) 1.00 (Reference) \n Allele G 91 (7.2) 39 (12.7) 1.90 (1.27-2.82) 0.0021 \nrs11568819 \n Allele C 1272 (100.0) 306 (100.0) 1.00 (Reference) -- \n Allele T 0 (0.0) 0 (0.0) -- \n \nCI: Confidence interval; OR: odds ratio. aChi-square test with Yates’ correction. Statistically significant p-values are shown in bold.\n\nand 143 patients with endometriosis (44). There was only one \nendometriosis case with GG genotype at MMP7 rs11568818. \nIn 2008, the contribution of MMP7 rs11568818 genotype to \nendometriosis was examined in a Caucasian population \ncontaining 241 controls and 227 endometriosis cases. The \nauthors found a negative association (45). In 2016, \nYarmolinskaya and colleagues provided another negative \nfinding in an extremely small cohort with only 45 controls and \n78 cases (46). Thus, although Yang and colleagues analyzed \nShan et al. ’s and Yarmolinskaya et al. ’s work in a meta-\nanalysis discussing the contribution of MMP7 rs11568818 \ngenotypes to endometriosis, the knowledge about the impacts \nof MMP7 genotypes on endometriosis is still controversial and \nfar from satisfying (47). \nAs shown in Table I, a notable finding is that the proportion \nof full-term pregnancy cases was significantly lower in the \nendometriosis group than in the control group (64.1% versus \n75.9%). On the other hand, there were no significant \ndifferences observed between the two groups with regards to \nsmoking and alcohol consumption behaviors. A previous study \nby Kim and colleagues reported that women with a family \nhistory of endometriosis and either smoking or early menarche \nhad a significantly increased risk of developing endometriosis \ncompared to the general population in Korea (55). However, \ndue to incomplete family history records of various cancer \ntypes or endometriosis, we were unable to investigate the \ninteraction between MMP7 rs11568818 genotypes and family \nhistory. Stratification analysis based on these factors (first full-\nterm pregnancy, smoking, alcohol drinking, and first menarche \nstatus) did not reveal any genotypic preferences in our \npopulation (all p>0.05, data not shown). These findings are \nconsistent with the meta-analysis conducted by Bravi and \ncolleagues, which reported no association between tobacco \nsmoking and endometriosis risk (56). We previously found \nthat human 8-oxoG DNA glycosylase 1 ( hOGG1) codon 326 \ngenotype may have a joint effect with smoking on the \ndevelopment of endometriosis (57). \nMMP7 is primarily responsible for the degradation of \nfibronectin, type IV collagen, laminin, nidogen, elastin, and \nβ4-integrin (14). These extracellular matrix components are \nproduced by various cancer cells, including breast, \ngastrointestinal, prostate, and endometrial tumor cells (58). \nMMP7 has been reported to be expressed by several types of \ncancer cells, such as lung (59), breast (60), head and neck \n(61), gastric (62), liver (63), pancreatic (64), colorectal (65) \nand most noticeable endometrial cancer (65). Thus, MMP7 is \nconsidered a practical marker and a potential therapeutic target \nfor intervention. However, the role of MMP7 genotype may \nvary significantly among different types of cancer, and the \nconclusions are still uncertain. In this study, we revealed the \nsignificant association of MMP7 genotype with endometriosis \nin a representative population in Taiwan for the first time. \nAlthough the genotypic findings require validation in diverse \npopulations, the phenotypic aspects proposed by Matsuzaki \nand colleagues must also be examined for more detailed \nmechanisms. Currently, it is only suggested that the epidermal \ngrowth factor receptor–MMP7 signaling pathway may be \ninvolved in the regulation of epithelial-mesenchymal transition \nduring endometriosis progression (66). \nOur results have provided an indication that MMP7 \nrs11568818 genotype might serve as a novel diagnosis \npredictor for endometriosis. More studies are urgently needed \nto reveal the possible critical regulation of ECM by MMPs, \nespecially MMP7, in regard to endometriosis etiology. \n \nConflicts of Interest \n \nThe Authors declare no conflicts of interest regarding this study. \n \nAuthors’ Contributions \n \nResearch design: Chien HJ, Bau DT, and Tsai CW; patient and \nquestionnaire summaries: Chien HJ, and Liu YF; experimental \nwork: Tsai CW, Chen JC, Wang YC and Yang YC; statistical \nanalysis: Hsieh YH, Yang YC and Tsai CW; article writing: Chang \nWS, Tsai CW, and Bau DT; article checking and discussion: Chien \nHJ, Wang YC, Chang WS, Hsieh YH, Liu YF, Yang YC, Chen JC, \nBau DT and Tsai CW. \n \nAcknowledgements \n \nThe Authors are grateful to Yu-Ting Chin and Hou-Yu Shih for their \nexcellent technical assistance. All the participants including those \nwho were not selected for the control group of the study are \nappreciated. 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DOI: 10.18632/oncotarget.11450 \n64 Jones LE, Humphreys MJ, Campbell F, Neoptolemos JP, Boyd \nMT: Comprehensive analysis of matrix metalloproteinase and \ntissue inhibitor expression in pancreatic cancer. Clin Cancer Res \n10(8): 2832-2845, 2004. DOI: 10.1158/1078-0432.ccr-1157-03 \n65 Matsuzaki S, Maleysson E, Darcha C: Analysis of matrix \nmetalloproteinase-7 expression in eutopic and ectopic endometrium \nsamples from patients with different forms of endometriosis. Hum \nReprod 25(3): 742-750, 2010. DOI: 10.1093/humrep/dep435 \n66 Chatterjee K, Jana S, DasMahapatra P, Swarnakar S: EGFR-\nmediated matrix metalloproteinase-7 up-regulation promotes \nepithelial-mesenchymal transition via ERK1-AP1 axis during \novarian endometriosis progression. FASEB J 32(8): 4560-4572, \n2018. DOI: 10.1096/fj.201701382RR \n \n \nReceived April 8, 2024 \nRevised May 6, 2024 \nAccepted May 8, 2024\nANTICANCER RESEARCH 44: 3051-3058 (2024)\n3058","source_license":"CC0","license_restricted":false}