Association of Matrix Metalloproteinase-1 Promoter Genotypes With Endometriosis Risk

Among the patients with endometriosis, the distribution of genotypes 2G/2G, 2G/1G, and 1G/1G at MMP-1 rs1799750 was 52.7%, 41.4%, and 5.9%, respectively. This distribution significantly differed from that of the control group, which exhibited frequencies of 41.3%, 48.3%, and 10.4%, respectively (p for trend=0.0092). In the dominant model, carriers of the 2G/1G and 1G/1G genotypes had a reduced prevalence in the endometriosis group compared to 2G/2G carriers [odds ratio (OR)=0.63, 95% confidence interval (95%CI)=0.46-0.87, p=0.0058]. Additionally, the 1G allele frequency in the endometriosis group was 26.6%, significantly lower than the 34.5% observed in controls (OR=0.69, 95%CI=0.54-0.88, p=0.0037). Conclusion: The 1G allele of MMP-1 rs1799750 is associated with reduced susceptibility to endometriosis in the Taiwanese population. These results highlight the potential of MMP-1 rs1799750 polymorphism as a protective genetic marker, warranting further investigations to explore its genotype- phenotype correlation and underlying biological mechanisms. Endometriosis is a chronic, hormone-dependent, and inflammatory gynecological condition, affecting up to 10% of women of reproductive age (1, 2). It is a complex disorder characterized by the growth of endometrial-like tissue outside the uterus, which can cause chronic pelvic pain and infertility (3, 4). In Taiwan, the reported prevalence of endometriosis has shown an upward trend, ranging from 1.5% to 30.8% among women of childbearing age (5-7). Moreover, women diagnosed with endometriosis exhibit an increased risk of developing several malignancies, including 465 #These Authors contributed equally to this study. Correspondence to: Jai-Sing Yang and Da-Tian Bau, Terry Fox Cancer Research Laboratory, China Medical University Hospital, 2 Yuh-Der Road, Taichung, 404 Taiwan, R.O.C. Tel: +886 422053366 Ext. 5805, e- mail: [email protected] (Bau DT); [email protected] (Yang JS) Key Words: Endometriosis, metalloproteinase-1, polymorphism, Taiwan. ANTICANCER RESEARCH 45: 465-471 (2025) doi:10.21873/anticanres.17436 Association of Matrix Metalloproteinase-1 Promoter Genotypes With Endometriosis Risk PO-CHUEN SHIEH 1#, HOU-YU SHIH 2,3#, CHIN-LIANG CHUANG 4,5#, CHIA-WEN TSAI 2,3, WEN-SHIN CHANG 2,3, MENG-GI BAU 3, YUN-CHI WANG2,3, TE-CHUN HSIA 3,6, DA-TIAN BAU 2,3,7 and JAI-SING YANG 3,8 1Department of Pharmacy, Tajen University, Pingtung, Taiwan, R.O.C.; 2Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.; 3Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 4Taichung Armed Forces General Hospital, Taichung, Taiwan, R.O.C.; 5National Defense Medical Center, Taipei, Taiwan, R.O.C.; 6Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 7Department of Bioinformatics and Medical Engineering, Asia University, Taichung, Taiwan, R.O.C.; 8Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan, R.O.C. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY-NC-ND) 4.0 international license (https://creativecommons.org/licenses/by-nc-nd/4.0). ©2025 The Author(s). Published by the International Institute of Anticancer Research. ovarian, endometrial, cervical, breast and colorectal cancers (8-13). The hypothesis of hereditary factors playing an important role is strongly supported by Bellelis and his colleagues, reporting that approximately 5.3% of the cases have first-degree family history (14). One important issue to consider is that endometriosis is a female disease characterized by notable heterogeneity and an unclear pathogenesis (15, 16). Thus, one of the major challenges is the lack of reliable predictive biomarkers (17, 18). Matrix metalloproteinases (MMPs) are a family of zinc- dependent endopeptidases that play a critical role in the degradation of extracellular matrix (ECM) components (19). Beyond ECM turnover, MMPs regulate fundamental cellular processes such as proliferation, differentiation, migration, and apoptosis, many of which are intricately linked to carcinogenic mechanisms (20). In the 1990s, MMPs were first identified as key mediators in uterine tissue remodeling during menstrual cycles and embryo implantation. Dysregulation of MMP activity was subsequently hypothesized to contribute to the pathogenesis of endometriosis (21-23). Over the past decades, heightened expression of matrix metalloproteinases (MMPs) has been consistently detected in ectopic tissues of individuals with endometriosis. This aberrant expression indicates a critical role for specific MMPs, such as MMP-2 (24, 25), MMP-3 (26), and MMP-9 (25, 27), in the pathogenesis and progression of the condition. Above all, MMP-1 has been highlighted for its significant involvement in endometriosis. Its expression correlates with the activity of endometriotic lesions, implicating it as a key factor in the pathophysiology of the condition (28, 29). The MMP-1 gene, located on chromosome 11q22.3, encodes the MMP-1 enzyme (30, 31) (Figure 1). Among its genetic variants, the rs1799750 polymorphism (rs796666299, rs375359915, rs368625565, rs139258005, rs17886084, and rs11292517 have been merged into the same polymorphism), situated 1607 base pairs upstream of the promoter region, has been the most intensively studied. This polymorphism has been found to be associated with specific types of cancer (32, 33), but not with others (34, 35). Numerous studies have explored the potential role of the MMP-1 rs1799750 polymorphism in predisposing individuals to endometriosis across different populations (36-39). Given these findings, we aimed to investigate the association between MMP-1 rs1799750 genotypes and the risk of endometriosis in a Taiwanese cohort comprising 203 patients with endometriosis and 636 non-endometriosis controls. This study examined the influence of MMP-1 polymorphisms on the susceptibility to endometriosis, thereby enhancing our understanding of the complex molecular mechanisms underlying the disease. Additionally, these findings may pave the way for novel approaches in the prevention and treatment of endometriosis. Patients and Methods Selection of endometriosis females and non-endometriosis controls. This study included a total of 203 women diagnosed with endometriosis and a matched cohort of 636 women without endometriosis as controls. Age-matching criteria were applied, with controls selected to be within ±5 years of the corresponding cases. All patients with endometriosis were recruited from China Medical University Hospital, located in central Taiwan. Participants were excluded from the control group if they had any history of leiomyoma, adenomyosis, or malignancies involving the uterus, cervix, or ovaries. Additionally, women who had undergone hormone therapy within the past 12 months were also excluded. To further reduce the possibility of misclassifying individuals with undiagnosed endometriosis as controls, a comprehensive screening process was implemented. Control candidates reporting symptoms such as pelvic pain or exhibiting signs suggestive of endometriosis during the questionnaire interview were referred for pelvic examinations, ultrasonography, or magnetic resonance imaging (MRI). Those with any findings indicative of endometriosis were subsequently excluded from the control group. Genotyping methodology for MMP-1 promoter polymorphisms. Peripheral blood samples were carefully obtained from all participants, with genomic DNA extracted within 24 h of collection following standard procedures (40, 41). Genotyping of the MMP-1 rs1799750 polymorphism was performed using a protocol previously described in detail (42). The polymerase chain reaction (PCR) conditions for MMP-1 rs1799750 analysis included an initial denaturation step at 94˚C for 5 min, followed by 35 cycles consisting of denaturation at 94˚C for 30 s, annealing at 57 ˚C for 30 s, and extension at 72 ˚C for 30 s. A final extension step was conducted at 72 ˚C for 10 min, after which the reaction was cooled and sustained to 25˚C. Statistical methodology. The adherence of the control group’s genotype frequencies to Hardy-Weinberg equilibrium (HWE) was evaluated using the goodness-of-fit Chi-square test. Differences in age distribution between cases and controls were analyzed with the Student’s t-test. Variations in the distribution of MMP-1 genotypes between endometriosis and non- endometriosis groups were assessed using the Pearson’s Chi-square test. To determine the association between MMP-1 genotypes and the risk of endometriosis, odds ratios (ORs) with corresponding 95% confidence intervals (CIs) were calculated. Statistical significance was defined as any p-value less than 0.05.

Demographic and lifestyle characteristics of study participants. Table I summarizes the demographic and lifestyle characteristics, including age, age at menarche, full-term pregnancy status, smoking habits, and alcohol consumption, for the 203 women diagnosed with endometriosis and the 636 non-endometriosis controls. Through careful age-matching, no significant differences were observed between the two groups in terms of age distribution (p=0.3732) or age at menarche ( p=0.3378). A significantly lower proportion of endometriosis patients (63.1%) reported having experienced a full-term pregnancy compared to the control group ( p=0.0005). In contrast, the prevalence of smoking and alcohol consumption did not differ significantly ANTICANCER RESEARCH 45: 465-471 (2025) 466 between the groups ( p=0.6470 and p=0.9387, respectively). Among the endometriosis cases, 21.2% were classified as early stage (Stage I or II), while the remaining 78.8% were categorized as advanced stage (Stage III or IV), as shown in Table I. Association of MMP-1 rs1799750 genotypes with endometriosis susceptibility. The distribution of MMP-1 rs1799750 genotypes among the 203 endometriosis cases and 636 non-endometriosis controls is comprehensively outlined in Table II. First, the genotype frequencies within the control group were consistent with Hardy-Weinberg equilibrium ( p=0.0870). Second, a comparative analysis revealed statistically significant differences in the overall distribution of MMP-1 rs1799750 genotypes between endometriosis cases and controls (p for trend=0.0092, Table II). Further evaluation indicated that the 2G/1G and 1G/1G genotypes were significantly less prevalent among endometriosis patients compared to controls, suggesting protective effects (OR=0.67, 95%CI=0.48-0.94, p=0.0226; and OR=0.45, 95%CI=0.23-0.86, p=0.0204, respectively; Table II). Additionally, when considering the combined genotypes 2G/2G+2G/1G compared to 1G/1G, a borderline statistical significance was observed (OR=0.54, 95%CI=0.29-1.03, p=0.0769). The association became more pronounced when contrasting 2G/2G with the pooled genotypes 2G/1G+1G/1G (OR=0.63, 95%CI=0.46-0.87, p=0.0058). Taken together, these findings indicate that individuals carrying the 1G/1G genotype exhibit a reduced risk of developing endometriosis in the Taiwanese population (Table II). Validation of the MMP-1 rs1799750 1G allele as protective against endometriosis. Table III details the allelic distribution of the MMP-1 rs1799750 polymorphism among endometriosis patients and non-endometriosis controls. Consistent with the genotype analysis presented in Table II, individuals carrying the 1G allele at the MMP-1 rs1799750 locus demonstrated a significantly reduced risk of developing endometriosis compared to those with the 2G allele (OR=0.69, 95%CI=0.54-0.88, p=0.0037, Table III). This

reinforces the protective role of the 1G allele in reducing susceptibility to endometriosis.

MMP-1 is a critical enzyme involved in the breakdown and remodeling of the extracellular matrix, processes closely linked to cellular migration and invasion (43, 44). The inhibition of MMP activity, including MMP-1, through the administration of MMP inhibitor III in a chicken chorioallantoic membrane model significantly suppressed the formation of endometriosis-like lesions. This finding underscores the potential contribution of MMP-1, along with MMP-2, -3, -7, and -13, to the development of endometriotic Shieh et al: MMP-1 Genotype in Endometriosis 467 Figure 1. Physical map of MMP-1 rs1799750 polymorphic site in human chromosome 11. lesions (45). Despite these insights, it remains unclear whether variations in MMP-1 expression are predominantly governed by genetic factors and whether the MMP-1 rs1799750 polymorphism could serve as a reliable predictive biomarker for endometriosis. Thus, in the present study, the potential impact of MMP-1 rs1799750 polymorphism on endometriosis susceptibility was meticulously examined in a Taiwan cohort, encompassing a cohort of 203 individuals with endometriosis and 636 age- matched non-endometriosis controls (Table I). The MMP-1 rs1799750 polymorphism has been hypothesized to generate an E-twenty six-binding site, potentially enhancing transcriptional activity (46). Previous investigations into the association between the MMP-1 rs1799750 polymorphism and endometriosis risk have yielded conflicting outcomes. First in 2005, Shan and his colleagues examined this polymorphism in a China cohort and reported that the 2G allele was significantly more prevalent among patients with endometriosis compared to controls. Additionally, they pointed out that the 2G/1G and 2G/2G genotypes were linked to an elevated risk of endometriosis (37). Similar findings were corroborated by Mao and his colleagues with a relatively smaller sample size (47). Conversely, Ferrari and his colleagues found no significant differences in allele or genotype frequencies between endometriosis patients and controls within an Italian cohort (38). Two years later, Borghese and his colleagues examined the contribution of MMP-1 rs1799750 genotypes to endometriosis among a French cohort, brought another piece of negative association evidence (39). The discrepancies between Shan’s results with Ferrari’s and Borghese’s findings may stem from several potential factors, including larger sample sizes in Shan’s study (37), a higher proportion of late- stage (III and IV) endometriosis cases, ethnic differences in the investigated populations (Asian versus Caucasian), and the genotyping methodology employed (PCR-RFLP). The work of Borghese even does not provide genotyping details, instead, they only presented the non-significant statistical outcomes (39). Despite these observations, the limitations of our study, such as sample size and the number of comparable studies, warrant cautious interpretation of the findings. All epidemiological studies examining the association between MMP-1 rs1799750 genotypes and endometriosis risk are summarized in Table IV , along with a concise summary of their highlight findings. Future studies with larger cohorts and more diverse populations are needed to confirm these results and clarify the role of the MMP-1 rs1799750 polymorphism in endometriosis susceptibility. The limited sample size also restricted us from further evaluating of MMP-1 rs1799750 genotypes to different (early and late) stages of endometriosis, which currently showed no preference (data not shown). This study represents the most extensive epidemiological investigation to date on the role of MMP-1 in the etiology of endometriosis, with a significantly larger scale compared to previous studies (control:case ratio of 636:203 in the present study versus smaller cohorts in prior reports) (Table IV). While the small sample sizes of earlier studies may have weakened the strength of their evidence, findings from Asian countries, consistently suggest that the 1G allele of MMP-1 rs1799750 functions as a protective genetic marker similar to our findings (Table II and Table III). In contrast, studies involving Western populations have generally indicated that the genotypes of MMP-1 rs1799750 lack the capacity as a practical biomarker for endometriosis prediction (Table IV). This dichotomy aligns with hypotheses proposed in meta- analysis review articles published in 2015 and 2016 (48, 49), highlighting the need for further research to draw definitive conclusions. Additionally, we examined the association of MMP-1 rs1799750 genotypes with various demographic and lifestyle factors, including age, age at menarche, full-term pregnancy status, smoking, and alcohol consumption. However, stratified analyses revealed no significant intergroup differences in these subcategories (data not shown). In conclusion, our findings suggest that the MMP-1 rs1799750 1G/1G genotype is associated with a reduced risk of endometriosis, and individuals possessing the 1G allele may experience a lower susceptibility to the condition. To establish its utility as a predictive biomarker, further validation of the MMP-1 rs1799750 variant is warranted across diverse populations, especially Asian populations. The findings may provide significant benefits in mitigating the prevalence of endometriosis in Taiwan. ANTICANCER RESEARCH 45: 465-471 (2025) 468 Table I. Demographics of the 203 females with endometriosis and 636 non-endometriosis controls. Characteristics Cases (n=203) Controls (n=636) p-Value N % N % Age (mean±SD) 40.9±4.7 41.2±4.5 0.3732 Menarche ≤12.8 110 54.2% 318 50.0% 0.3378 >12.8 93 45.8% 318 50.0% Full-term pregnancy No 75 36.9% 153 24.1% 0.0005* Yes 128 63.1% 483 75.9% Smoking status Non-smokers 148 72.9% 476 74.8% 0.6470 Smokers 55 27.1% 160 25.2% Alcohol drinking status Non-drinkers 149 73.4% 463 72.8% 0.9387 Drinkers 54 26.6% 173 27.2% Stage I or II 43 21.2% III or IV 160 78.8% Statistical analysis was based on Pearson’s chi-square with Yates’ correction test; *statistically significant. Conflicts of Interest The Authors have no conflicts of interest to declare in relation to this study. Authors’ Contributions Research design: Shieh PC, Yang JS, Bau DT; Summary of questionnaires: Shih HY , Chuang CL, Hsia TC; Experiment performance: Shih HY , Yang JS, Tsai CW, Chang WS; Statistical analysis and confirmation: Shih HY , Wang YC, Tsai CW, Bau MG, Hsia TC; Manuscript writing: Shieh PC, Chuang CL, Yang JS, Bau DT; Polishing and correction: Yang JS, Bau DT.

The Authors are grateful to Yu-Hsin Yen and Yu-Cheng Luo for their excellent technical assistance. All the participants in this study are also appreciated. This study was supported by Taichung Armed Forces General Hospital (grant number: TCAFGH_D_114015), and China Medical University and Hospital (grand number: DMR-114- 098).

1 Adilbayeva A, Kunz J: Pathogenesis of endometriosis and endometriosis-associated cancers. Int J Mol Sci 25(14): 7624, 2024. DOI: 10.3390/ijms25147624 Shieh et al: MMP-1 Genotype in Endometriosis 469 Table IV . Summary of previous and current studies focusing on the association of MMP-1 rs1799750 with endometriosis. First author Publication Investigated Genotypes Genotypes Highlight Reference year ethnics of the cases a of the controls a findings number Shieh 2025 Taiwan 107:84:12 263:307:66 The 1G/1G genotype is protective Current Mao 2012 China 20:8:2 16:11:5 The 1G/1G genotype is protective (47) Borghese 2008 France Not available Not available No significant association (39) Ferrari 2006 Italy 16:27:13 21:32:18 No significant association (38) Shan 2005 China 65:28:7 76:49:25 The 1G/1G genotype is protective (37) aThe order of genotypes is 2G/2G:2G/1G:1G/1G. Table II. Distributions of MMP-1 rs1799750 genotypes in females with endometriosis and non-endometriosis controls. Genotype Endometriosis, n (%) Non-Endometriosis, n (%) OR (95%CI) p-Valuea rs1799750 2G/2G 107 (52.7) 263 (41.3) 1.00 (Reference) 2G/1G 84 (41.4) 307 (48.3) 0.67 (0.48-0.94) 0.0226* 1G/1G 12 (5.9) 66 (10.4) 0.45 (0.23-0.86) 0.0204* ptrend 0.0092* pHWE 0.0870 Carrier analysis 2G/2G+2G/1G 191 (94.1) 570 (89.6) 1.00 (Reference) 1G/1G 12 (5.9) 66 (10.4) 0.54 (0.29-1.03) 0.0769 2G/2G 107 (52.7) 263 (41.3) 1.00 (Reference) 2G/1G+1G/1G 96 (47.3) 373 (58.7) 0.63 (0.46-0.87) 0.0058* OR: Odds ratio; CI: confidence interval; HWE: Hardy-Weinberg Equilibrium; ptrend: p-Value for trend analysis; pHWE: p-Value for Hardy-Weinberg equilibrium analysis; aBased on Chi-square test with Yates’ correction; *statistically significant. Table III. Distribution of MMP-1 rs1799750 allelic frequencies in females with endometriosis and non-endometriosis controls. Allelic type Endometriosis, n (%) Non-Endometriosis, n (%) OR (95%CI) p-Valuea rs1799750 Allele 2G 298 (73.4) 833 (65.5) 1.00 (Reference) Allele 1G 108 (26.6) 439 (34.5) 0.69 (0.54-0.88) 0.0037* OR: Odds ratio; CI: confidence interval. aBased on Chi-square test with Yates’ correction; *statistically significant. 2 Jiang T, Chen Y , Gu X, Miao M, Hu D, Zhou H, Chen J, Teichmann AT, Yang Y: Review of the potential therapeutic effects and molecular mechanisms of resveratrol on endometriosis. Int J Womens Health 15: 741-763, 2023. DOI: 10.2147/IJWH.S404660 3 Leone Roberti Maggiore U, Chiappa V , Ceccaroni M, Roviglione G, Savelli L, Ferrero S, Raspagliesi F, Spanò Bascio L: Epidemiology of infertility in women with endometriosis. Best Pract Res Clin Obstet Gynaecol 92: 102454, 2024. DOI: 10.1016/j.bpobgyn.2023.102454 4 Yang S, Wang H, Li D, Li M: An estrogen-NK cells regulatory axis in endometriosis, related infertility, and miscarriage. Int J Mol Sci 25(6): 3362, 2024. DOI: 10.3390/ijms25063362 5 Chiang AJ, Chang C, Huang CH, Huang WC, Kan YY , Chen J: Risk factors in progression from endometriosis to ovarian cancer: a cohort study based on medical insurance data. J Gynecol Oncol 29(3): e28, 2018. DOI: 10.3802/jgo.2018.29.e28 6 Lee WL, Chang WH, Wang KC, Guo CY , Chou YJ, Huang N, Huang HY , Yen MS, Wang PH: The risk of epithelial ovarian cancer of women with endometriosis may be varied greatly if diagnostic criteria are different: a nationwide population-based cohort study. Medicine (Baltimore) 94(39): e1633, 2015. DOI: 10.1097/MD.0000000000001633 7 Chang WH, Wang KC, Lee WL, Huang N, Chou YJ, Feng RC, Yen MS, Huang BS, Guo CY , Wang PH: Endometriosis and the subsequent risk of epithelial ovarian cancer. Taiwan J Obstet Gynecol 53(4): 530-535, 2014. DOI: 10.1016/j.tjog.2014.04.025 8 Wang KC, Chang WH, Lee WL, Huang N, Huang HY , Yen MS, Guo CY , Wang PH: An increased risk of epithelial ovarian cancer in Taiwanese women with a new surgico-pathological diagnosis of endometriosis. BMC Cancer 14: 831, 2014. DOI: 10.1186/1471-2407-14-831 9 Terry KL, Harris HR, Missmer SA: Endometriosis and ovarian cancer. JAMA 332(24): 2116, 2024. DOI: 10.1001/jama. 2024.21905 10 Steinbuch SC, Lüß AM, Eltrop S, Götte M, Kiesel L: Endometriosis-associated ovarian cancer: from molecular pathologies to clinical relevance. Int J Mol Sci 25(8): 4306, 2024. DOI: 10.3390/ijms25084306 11 Vanni G, Selntigia A, Marsella VE, Russo C, Pellicciaro M, Materazzo M, Rizzo G, Buonomo OC, Exacoustos C: Breast cancer in patients with previous endometriosis showed low aggressive subtype. Medicina (Kaunas) 60(4): 625, 2024. DOI: 10.3390/medicina60040625 12 Al-Badawi IA, Abu-Zaid A, Alomar O, Alsabban M, Alsehaimi SO, Alqarni SMS, Alabdrabalamir SN, Baradwan S, Al Baalharith M, AlOdaini AA, Saleh SAK, Adly HM, Bukhari IA, Salem H: Association between endometriosis and the risk of ovarian, endometrial, cervical, and breast cancer: a population-based study from the U.S. National Inpatient Sample 2016-2019. Curr Oncol 31(1): 472-481, 2024. DOI: 10.3390/curroncol31010032 13 Wu C, Wei MYK, Yeung JMC, Battye S, Cho J: Deep infiltrating endometriosis mimicking colorectal cancer. ANZ J Surg 93(11): 2751-2753, 2023. DOI: 10. 1111/ans.18525 14 Bellelis P, Dias JA Jr, Podgaec S, Gonzales M, Baracat EC, Abrão MS: Epidemiological and clinical aspects of pelvic endometriosis-a case series. Rev Assoc Med Bras (1992) 56(4): 467-471, 2010. DOI: 10.1590/s0104-42302010000400022 15 Jiang L, Wang S, Xia X, Zhang T, Wang X, Zeng F, Ma J, Fang X: Novel Diagnostic Biomarker BST2 Identified by Integrated Transcriptomics Promotes the Development of Endometriosis via the TNF-α/NF-ĸB Signaling Pathway. Biochem Genet, 2024. DOI: 10.1007/s10528-024-10666-z 16 Zhu S, Wang A, Xu W, Hu L, Sun J, Wang X: The heterogeneity of fibrosis and angiogenesis in endometriosis revealed by single- cell RNA-sequencing. Biochim Biophys Acta Mol Basis Dis 1869(2): 166602, 2023. DOI: 10.1016/j.bbadis.2022.166602 17 Zygula A, Kiecka K, Sankiewicz A, Kuzmicki M, Ciebiera M, Issat T, Drygas W, Cendrowski K, Gorodkiewicz E, Laudanski P: Is osteopontin a reliable biomarker for endometriosis? Int J Mol Sci 25(22): 11857, 2024. DOI: 10.3390/ijms252211857 18 Zygu ła A, Sankiewicz A, Sakowicz A, Dobrzy ńska E, Dakowicz A, Ma ńka G, Kiecka M, Spaczynski R, Piekarski P, Banaszewska B, Jakimiuk A, Issat T, Rokita W, M łodawski J, Szubert M, Sieroszewski P, Raba G, Szczupak K, Kluza T, Kluza M, Pierzy ński P, Wojtyla C, Lipa M, Warzecha D, Wielgos M, Cendrowski K, Gorodkiewicz E, Laudanski P: Is the leptin/BMI ratio a reliable biomarker for endometriosis? Front Endocrinol (Lausanne) 15: 1359182, 2024. DOI: 10.3389/fendo.2024.1359182 19 Mustafa S, Koran S, AlOmair L: Insights into the role of matrix metalloproteinases in cancer and its various therapeutic aspects: a review. Front Mol Biosci 9: 896099, 2022. DOI: 10.3389/fmolb.2022.896099 20 Tang L, Xiang Y , Zhou Y , Mu J, Zai M, Xing Q, Zhao X, He L, Wang L, Dong X, Li Q: The DNA methylation status of genes encoding Matrix metalloproteinases and tissue inhibitors of Matrix metalloproteinases in endometriosis. Mol Reprod Dev 85(1): 17-25, 2018. DOI: 10.1002/mrd.22931 21 Simón C, Gimeno MJ, Mercader A, Francés A, Garcia Velasco J, Remohí J, Polan ML, Pellicer A: Cytokines-adhesion molecules-invasive proteinases. The missing paracrine/autocrine link in embryonic implantation? Mol Hum Reprod 2(6): 405- 424, 1996. DOI: 10.1093/molehr/2.6.405 22 Tabibzadeh S: The signals and molecular pathways involved in human menstruation, a unique process of tissue destruction and remodelling. Mol Hum Reprod 2(2): 77-92, 1996. DOI: 10.1093/molehr/2.2.77 23 Osteen KG, Bruner KL, Sharpe-Timms KL: Steroid and growth factor regulation of matrix metalloproteinase expression and endometriosis. Semin Reprod Endocrinol 14(03): 247-255, 1996. DOI: 10.1055/s-2007-1016334 24 Chung HW, Lee JY , Moon HS, Hur SE, Park MH, Wen Y , Polan ML: Matrix metalloproteinase-2, membranous type 1 matrix metalloproteinase, and tissue inhibitor of metalloproteinase-2 expression in ectopic and eutopic endometrium. Fertil Steril 78(4): 787-795, 2002. DOI: 10.1016/s0015-0282(02)03322-8 25 Shaco-Levy R, Sharabi S, Benharroch D, Piura B, Sion-Vardy N: Matrix metalloproteinases 2 and 9, E-cadherin, and β-catenin expression in endometriosis, low-grade endometrial carcinoma and non-neoplastic eutopic endometrium. Eur J Obstet Gynecol Reprod Biol 139(2): 226-232, 2008. DOI: 10.1016/j.ejogrb.2008.01.004 26 Cox KE, Piva M, Sharpe-Timms KL: Differential regulation of matrix metalloproteinase-3 gene expression in endometriotic lesions compared with endometrium. Biol Reprod 65(4): 1297- 1303, 2001. DOI: 10.1095/biolreprod65.4.1297 27 Szamatowicz J, Lauda ński P, Tomaszewska I: Matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase- 1: a possible role in the pathogenesis of endometriosis. Hum Reprod 17(2): 284-288, 2002. DOI: 10.1093/humrep/17.2.284 ANTICANCER RESEARCH 45: 465-471 (2025) 470 28 Kokorine I, Nisolle M, Donnez J, Eeckhout Y , Courtoy PJ, Marbaix E: Expression of interstitial collagenase (matrix metalloproteinase-1) is related to the activity of human endometriotic lesions. Fertil Steril 68(2): 246-251, 1997. DOI: 10.1016/s0015-0282(97)81510-5 29 Huang Y , Shen L, Cai A, Xiao J: Effect of warming Yang and removing blood stasis method on matrix metalloproteinases / tissue inhibitor metalloproteinases levels secreted by cultured endometrial cells from patients with endometriosis. J Tradit Chin Med 35(5): 571-576, 2015. DOI: 10.1016/s0254-6272(15)30141-2 30 Pendás AM, Santamaría I, Alvarez MV , Pritchard M, López-Otín C: Fine physical mapping of the human matrix metalloproteinase genes clustered on chromosome 11q22.3. Genomics 37(2): 266- 268, 1996. DOI: 10.1006/geno.1996.0557 31 Cheng YC, Kao WH, Mitchell BD, O’Connell JR, Shen H, McArdle PF, Gibson Q, Ryan KA, Shuldiner AR, Pollin TI: Genome-wide association scan identifies variants near Matrix Metalloproteinase (MMP) genes on chromosome 11q21-22 strongly associated with serum MMP-1 levels. Circ Cardiovasc Genet 2(4): 329-337, 2009. DOI: 10.1161/CIRCGENETICS.108.834986 32 Wu MH, Yueh TC, Chang WS, Tsai CW, Fu CK, Yang MD, Yu CC, Bau DT: Contribution of matrix metalloproteinase-1 genotypes to colorectal cancer in Taiwan. Cancer Genomics Proteomics 18(3): 245-251, 2021. DOI: 10.21873/cgp.20255 33 Lai YL, Gong CL, Fu CK, Yueh TC, Tsai CW, Chang WS, Hsiao CL, Yen ST, Li HT, Jeng LB, Wang SC, Bau DT: The contribution of matrix metalloproteinase-1 genotypes to hepatocellular carcinoma susceptibility in Taiwan. Cancer Genomics Proteomics 14(2): 119-125, 2017. DOI: 10.21873/cgp.20024 34 Liao CH, Tsai CW, Chang WS, Wang ZH, Gong CL, Wu HC, Wang BR, Hsu SW, Huang WC, Shen TC, Bau DT: Association of matrix metalloproteinase-1 genotypes with bladder cancer risk. In Vivo 35(5): 2535-2540, 2021. DOI: 10.21873/invivo.12535 35 Liao CH, Wu HC, Hu PS, Hsu SW, Shen TC, Hsia TC, Chang WS, Tsai CW, Bau DT: The association of matrix metalloproteinase-1 promoter polymorphisms with prostate cancer in Taiwanese patients. Anticancer Res 38(7): 3907-3911, 2018. DOI: 10.21873/anticanres.12675 36 Kang S, Wang Y , Zhang JH, Jin X, Fang SM, Li Y: [Single nucleotide polymorphism in the matrix metalloproteinases promoter is associated with susceptibility to endometriosis and adenomyosis]. Zhonghua Fu Chan Ke Za Zhi 40(9): 601-604, 2005. 37 Shan K, Ying W, Jian-Hui Z, Wei G, Na W, Yan L: The function of the SNP in the MMP1 and MMP3 promoter in susceptibility to endometriosis in China. Mol Hum Reprod 11(6): 423-427, 2005. DOI: 10.1093/molehr/gah177 38 Ferrari MM, Biondi ML, Rossi G, Grijuela B, Gaita S, Perugino G, Viganò P: Analysis of two polymorphisms in the promoter region of matrix metalloproteinase 1 and 3 genes in women with endometriosis. Acta Obstet Gynecol Scand 85(2): 212-217, 2006. DOI: 10.1080/00016340500345287 39 Borghese B, Chiche JD, Vernerey D, Chenot C, Mir O, Bijaoui G, Bonaiti-Pellie C, Chapron C: Genetic polymorphisms of matrix metalloproteinase 12 and 13 genes are implicated in endometriosis progression. Hum Reprod 23(5): 1207-1213, 2008. DOI: 10.1093/humrep/den007 40 Yang MD, Lin KC, Lu MC, Jeng LB, Hsiao CL, Yueh TC, Fu CK, Li HT, Yen ST, Lin CW, Wu CW, Pang SY , Bau DT, Tsai FJ: Contribution of matrix metalloproteinases-1 genotypes to gastric cancer susceptibility in Taiwan. Biomedicine (Taipei) 7(2): 10, 2017. DOI: 10.1051/bmdcn/2017070203 41 Chen CC, Tsai CL, Pei JS, Tzeng HE, Hsu PC, Cheng DC, Lin JC, Tsai CW, Bau DT, Chang WS: Contribution of cyclin dependent kinase inhibitor 1A genotypes to childhood acute lymphocytic leukemia risk in Taiwan. Cancer Genomics Proteomics 22(1): 46-54, 2025. DOI: 10.21873/cgp.20486 42 Chen LH, Li CH, Wang SC, Chiu KL, Wu MF, Yang JS, Tsai CW, Chang WS, Hsia TC, Bau DT: Association of matrix metalloproteinase-1 promoter polymorphisms with asthma risk. In Vivo 38(1): 365-371, 2024. DOI: 10.21873/invivo.13447 43 Braundmeier AG, Fazleabas AT, Nowak RA: Extracellular matrix metalloproteinase inducer expression in the baboon endometrium: menstrual cycle and endometriosis. Reproduction 140(6): 911-920, 2010. DOI: 10.1530/REP-09-0481 44 Maoga JB, Riaz MA, Mwaura AN, Mecha E, Omwandho COA, Scheiner-Bobis G, Meinhold-Heerlein I, Konrad L: Analysis of membrane type-1 matrix metalloproteinase (MT1-MMP, MMP14) in eutopic and ectopic endometrium and in serum and endocervical mucus of endometriosis. Biomedicines 11(10): 2730, 2023. DOI: 10.3390/biomedicines11102730 45 Nap AW, Dunselman GA, de Goeij AF, Evers JL, Groothuis PG: Inhibiting MMP activity prevents the development of endometriosis in the chicken chorioallantoic membrane model. Hum Reprod 19(10): 2180-2187, 2004. DOI: 10.1093/humrep/deh408 46 Pereza N, Pleša I, Peterlin A, Jan Ž, Tul N, Kapović M, Ostojić S, Peterlin B: Functional polymorphisms of matrix metalloproteinases 1 and 9 genes in women with spontaneous preterm birth. Dis Markers 2014: 171036, 2014. DOI: 10.1155/2014/171036 47 Mao W, Wu J, Zhang B: The function of MMPs polymorphisms and expression in endometriosis. Matern Child Health Care China 34: 5588-5589, 2012. 48 Yang H, Liu J, Fan Y , Guo Q, Ge L, Yu N, Zheng X, Dou Y , Zheng S: Associations between various possible promoter polymorphisms of MMPs genes and endometriosis risk: a meta- analysis. Eur J Obstet Gynecol Reprod Biol 205: 174-188, 2016. DOI: 10.1016/j.ejogrb.2016.08.015 49 Trovó de Marqui AB: Genetic polymorphisms and endometriosis: contribution of genes that regulate vascular function and tissue remodeling. Rev Assoc Med Bras (1992) 58(5): 620-632, 2012. DOI: 10.1590/s0104-42302012000500022 Received January 3, 2025 Revised January 14, 2025 Accepted January 15, 2025 Shieh et al: MMP-1 Genotype in Endometriosis 471