Contribution of Matrix Metalloproteinase-7 Genotypes to Endometriosis Risk in Taiwan

The statistical analysis revealed that MMP7 rs11568818 genotypes were differentially distributed between the endometriosis and control groups (p for trend=0.0048). Specifically, the MMP7 rs11568818 homozygous variant GG was associated with endometriosis risk compared to the wild- type AA genotype (OR=4.59, 95% CI=1.46-14.48, p=0.0136). However, the MMP7 rs11568818 heterozygous variant AG was not associated with endometriosis risk (OR=1.57, 95% CI=0.97-2.53, p=0.0854). The frequency of than variant allele G of MMP7 rs11568818 was 12.7% in the endometriosis group, significantly higher than the 7.2% observed in the control group (OR=1.90, 95% CI=1.27-2.82, p=0.0021).

MMP7 rs11568818 GG genotype was found to be a novel marker for endometriosis risk in Taiwanese. Endometriosis is a hormone-dependent, inflammatory, benign gynecological disease characterized by the growth of endometrial cells outside the uterus (1, 2). It is a significant health concern affecting approximately 10% of women of reproductive age globally (3). In Taiwan, the prevalence of endometriosis has been observed to have increased in recent years, with estimated rates ranging from 1.5% to 30.8% among women of reproductive age (4-6). Women with endometriosis have an elevated risk of developing ovarian, breast, endocrine, and colorectal cancer (7, 8). Clinical features include dysmenorrhea, chronic pelvic pain, painful intercourse, and infertility (2). Although the etiology of endometriosis remains incompletely understood, accumulating evidence suggests that it is a multifactorial disease involving inflammation, hormonal dysregulation, and genetic factors (9-11). The matrix metalloproteinases (MMPs) are a group of peptidases that play a critical role in inflammation, carcinogenesis, and cancer cell migration through the regulation of extracellular matrix (ECM) components (12, 13). MMP7 is normally expressed in bronchial, ductal, skin glandular, 3051 *These Authors contributed equally to this study. Correspondence to: 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]; Chia-Wen Tsai, 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] Key Words: Endometriosis, genotype, MMP7, polymorphism, Taiwan. ANTICANCER RESEARCH 44: 3051-3058 (2024) doi:10.21873/anticanres.17118 Contribution of Matrix Metalloproteinase-7 Genotypes to Endometriosis Risk in Taiwan HUNG-JU CHIEN 1,2, YUN-CHI WANG3,4, WEN-SHIN CHANG 3,4, YI-HSIEN HSIEH 1, YEN-FANG LIU5, YA-CHEN YANG6, JAW-CHYUN CHEN7, DA-TIAN BAU 3,4,8* and CHIA-WEN TSAI 3,4* 1Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, R.O.C.; 2Department of Obstetrics and Gynecology, Changhua Christian Hospital, Changhua, Taiwan, R.O.C.; 3Graduate Institute of Biomedical Sciences, China Medical University, Taichung, Taiwan, R.O.C.; 4Terry Fox Cancer Research Laboratory, Department of Medical Research, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 5Department of Nursing, China Medical University Hospital, Taichung, Taiwan, R.O.C.; 6Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan, R.O.C.; 7Department of Medicinal Botanicals and Foods on Health Applications, Da-Yeh University, Changhua, Taiwan, R.O.C.; 8Department of Bioinformatics and Medical Engineering, Asia 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). urogenital, gastrointestinal, and especially endometrial tissues (14). Conversely, low levels of MMP7 expression are reported in lung, gallbladder, and bladder tissues, and normally ultra-low levels of MMP7 are upregulated in abnormal conditions, such as malignant tumorigenesis (15-17). As evidenced by the literature, MMP7 is responsible for cleaving a variety of ECM proteins, including collagen IV , fibronectin, laminin, and tenascin-C, as well as non-ECM proteins, such as E-cadherin, tumor necrosis factor-α, and other MMP family members (14, 18-22). Thus, MMP7 plays a crucial role in maintaining the balance of many cellular processes, including cell growth, inflammation, wound healing, cell remodeling, carcinogenesis, and angiogenesis (23-27). Moreover, MMP7 is specifically expressed in multiple tumor types, such as digestive (28), urinary (29, 30), and reproductive (31) system tumors. By inhibiting apoptosis of cancer cells (32), reducing cell adhesion (33), and inducing angiogenesis (34), MMP7 promotes tumor progression and functions as an oncogenic protein that regulates the occurrence and development of various tumors. Among these MMPs, the gene for MMP7 is located on human chromosome 11 q22.3 and consists of 13 exons (35). In terms of the genotype–phenotype correlation, increased MMP7 activity was observed in promoter constructs containing the MMP7 rs11568818 and rs11568819 variant alleles (36). Previous literature has examined the association of MMP7 genotypes with various cancer types, such as oral, esophageal, gastric, colorectal, gallbladder, lung, breast, bladder and prostate, astrocytoma, renal cell carcinoma, and childhood leukemia (37-43). However, the investigation of MMP7 genotypes in relation to endometriosis is extremely limited. At the time of writing, there were only four reports (44-47). Based on the aforementioned information, our study aimed to assess the potential correlation between MMP7 rs11568818 and rs11568819 genotypes and the risk of developing endometriosis in a Taiwanese cohort consisting of 153 patients with endometriosis and 636 healthy controls. The selected MMP7 polymorphic sites are illustrated in Figure 1. Patients and Methods Recruitment of patients with endometriosis and non-endometriosis control groups. One hundred and fifty-three individuals diagnosed with endometriosis were enrolled at China Medical University Hospital between 2000 and 2010. The doctors confirmed the diagnosis of endometriosis and classified the cases according to the guidelines established by the American Society for Reproductive Medicine (48). Participants were excluded if they had leiomyoma, adenomyosis, or any uterine, cervical, or ovarian cancer, and if they had received hormone therapy within the preceding 12 months. The basal follicle-stimulating hormone level was 7.2±1.4 IU/l. All patients provided written informed consent and donated 5 mL of peripheral blood for DNA extraction and genotyping analyses. Additionally, 636 healthy individuals without endometriosis were recruited as controls. To minimize the likelihood of including individuals with endometriosis in the control group, potential controls who reported any symptoms (such as pelvic pain) or had suspicion of endometriosis during our questionnaire interview were recommended for pelvic exams, ultrasound, or magnetic resonance imaging and excluded from the control group. However, we acknowledge that some controls may still have had undiagnosed endometriosis, as up to 16-20% of patients with endometriosis may be asymptomatic (4-6). Regarding the questionnaire, we collected and kept confidential information about participants’ personal smoking and drinking habits, age of menarche, and pregnancy history. We defined smokers as individuals who had smoked at least five packs of cigarettes in their lifetime and reported smoking on a daily or almost daily basis. Smokers were also asked about the age at which they began smoking, whether they continued smoking or had quit, and if so, when they quit. Furthermore, they were asked to report their average daily cigarette consumption. Non- drinkers were classified as individuals who consumed less than 200 mL of alcohol per week and consumed alcohol less than twice per month for social purposes. MMP7 genotyping methodology. The DNA extraction procedure utilized in this study involved the use of the QIAamp Blood Mini Kit (Blossom, Taipei, Taiwan, ROC) to extract peripheral blood leukocytes from each participant, as described in prior publications (49, 50). The primer design, selection of corresponding restriction endonucleases, and polymerase chain reaction conditions for genotyping of MMP7 were consistent with those employed in our previous publication (51). The genotyping procedure was conducted independently and in a double-blind manner by at least two well- trained researchers, with each genotypic analysis being repeated multiple times. The results of all repeated genotyping analyses were found to be 100% concordant with one another. Statistical analyses. Age indices between the endometriosis case and control groups were compared using Student’s t-test. Distribution of the MMP7 genotypes among analyzed subgroups was assessed using Pearson’s chi-square test. The contribution of MMP7 genotypes to endometriosis risk was evaluated using odds ratios (ORs) and their associated 95% confidence intervals (CIs). Statistical significance was defined as a p-value of less than 0.05.

Demographic characteristics of the investigated population. Table I presents the frequency distributions of age, age at menarche, full-term pregnancy, smoking and alcohol consumption status, and clinical stages of endometriosis in 153 patients with endometriosis and 636 healthy controls without endometriosis. The cases had a mean age of 40.3±4.9 years, and 55 (35.9%) of them had not experienced a full-term pregnancy. Among the patients, 32 (20.9%) had minimal or mild endometriosis (stage I or II), while 121 (79.1%) had moderate or severe endometriosis (stage III or IV) according to the revised American Fertility Society classification (48). No significant difference was observed in age at menarche and smoking and alcohol consumption status between cases and controls ( p>0.05). However, the percentage of full-term pregnancies was significantly lower (p=0.0041) among patients with endometriosis (64.1%) than among women without endometriosis (75.9%) (Table I). ANTICANCER RESEARCH 44: 3051-3058 (2024) 3052 MMP7 genotyping outcomes. Table II presents the distribution of MMP7 rs11568818 and rs11568819 genotypes among 153 endometriosis cases and 636 healthy controls. The results revealed that the MMP7 rs11568818 genotypes were differentially distributed between the endometriosis and control groups (p for trend=0.0048) (Table II). Specifically, the MMP7 rs11568818 homozygous GG variant was found to be associated with an increased risk of endometriosis compared to the wild- type AA genotype (OR=4.59, 95% CI=1.46-14.48, p=0.0136, Table II). However, the MMP7 rs11568819 heterozygous AG variant was not associated with endometriosis risk (OR=1.57, 95% CI=0.97-2.53, p=0.0854, Table II). In the dominant model, the data demonstrated that the frequency of MMP7 rs11568818 G allele-bearing genotypes was significantly higher in the endometriosis group than in the healthy control group (21.6% versus 13.4%, respectively; OR=1.78, 95% CI=1.14-2.79, Chien et al: MMP7 Genotype in Endometriosis 3053 Figure 1. The polymorphic sites of matrix metalloproteinase-7 (MMP7) rs11568818 and rs11568819 on chromosome 11. Table I. Demographics of the 153 endometriosis and 636 healthy controls. Characteristic Cases (n=153) Controls (n=636) p-Value N % N % Age (mean±SD) 40.3±4.9 41.2±4.5 0.8865 Age at menarche ≥12.8 Years 85 55.6% 318 50.0% 0.2418 >12.8 Years 68 44.4% 318 50.0% Full-term pregnancy No 55 35.9% 153 24.1% 0.0041 Yes 98 64.1% 483 75.9% Smoking status Non-smokers 113 73.9% 476 74.8% 0.8361 Smokers 40 26.1% 160 25.2% Alcohol drinking status Non-drinkers 116 75.8% 463 72.8% 0.4772 Drinkers 37 24.2% 173 27.2% Stage I or II 32 20.9% III or IV 121 79.1% Statistical analysis was based on Pearson’s chi-square with Yates’ correction test. Statistically significant p-values are shown in bold. p=0.0001, Table II). It is worth noting that all individuals had the CC genotype at the rs11568819 polymorphic site, without any CT or TT genotype carriers (Table II). MMP7 allelic frequency distribution. Consistent with the

in Table II, the frequency of the MMP7 rs11568818 variant allele G was 12.7% in the endometriosis group, which was significantly higher than the 7.2% observed in the control group (OR=1.90, 95% CI=1.27-2.82, p=0.0021, Table III). Furthermore, the allelic frequency of MMP7 rs11568819 was 100% for the C allele in both the case and control groups (Table III).

MMP7 was initially reported to be expressed primarily in epithelial endometrial cells in 1993 (52). Subsequently, accumulating evidence has demonstrated that the levels of various MMPs, such as MMP2 and MMP9, are increased in the ectopic tissues and peritoneal fluids of patients with endometriosis (53). Nevertheless, only a limited number of studies have investigated the involvement of MMP7 in the pathogenesis of endometriosis, and its genetic contribution has not yet to be thoroughly examined (54). In this case–control study, we investigated MMP7 genotype profiles in a representative Taiwanese population of 789 individuals, comprising 153 endometriosis cases and 636 non- endometriosis controls (as shown in Table I). Our study is the first to evaluate the contribution of MMP7 genotypes to endometriosis risk among Taiwanese. One of the significant findings is that MMP7 rs11568818 genotypes were differentially distributed between the endometriosis and control groups (as presented in Table II), suggesting that the GG and AG genotypes of MMP7 rs11568818 could potentially serve as novel diagnostic predictors for endometriosis. Notably, the G allele of MMP7 rs11568818 has been identified as an effective biomarker for endometriosis worldwide. In 2006, Shan and colleagues reported that variant (GG and AG) genotypes of MMP7 rs11568818 were a risk factor for endometriosis in a Chinese population containing 160 controls ANTICANCER RESEARCH 44: 3051-3058 (2024) 3054 Table II. Genotypic frequency distributions of matrix metalloproteinase-7 rs11568818 and rs11568819 among the 153 endometriosis cases and 636 healthy controls. Genotype Controls, n (%) Cases, n (%) OR (95%CI) p-Valuea rs11568818 AA 551 (86.6) 120 (78.4) 1.00 (Reference) AG 79 (12.4) 27 (17.7) 1.57 (0.97-2.53) 0.0854 GG 6 (1.0) 6 (3.9) 4.59 (1.46-14.48) 0.0136 AG+GG 85 (13.4) 33 (21.6) 1.78 (1.14-2.79) 0.0001 ptrend 0.0048 pHWE 0.1013 rs11568819 CC 636 (100.0) 153 (100.0) 1.00 (Reference) -- CT 0 (0.0) 0 (0.0) -- TT 0 (0.0) 0 (0.0) -- pHWE 1.0000 CI: Confidence interval; OR: odds ratio. aChi-square test with Yates’ correction; ptrend: p-value based on trend analysis; pHWE: p-value based on Hardy–Weinberg equilibrium. Statistically significant p-values are shown in bold. Table III. Allelic frequencies for matrix metalloproteinase-7 rs11568818 and rs11568819 polymorphisms among the endometriosis cases and h ealthy controls. Genotype Controls, n (%) Cases, n (%) OR (95%CI) p-Valuea rs11568818 Allele A 1181 (92.8) 267 (87.3) 1.00 (Reference) Allele G 91 (7.2) 39 (12.7) 1.90 (1.27-2.82) 0.0021 rs11568819 Allele C 1272 (100.0) 306 (100.0) 1.00 (Reference) -- Allele T 0 (0.0) 0 (0.0) -- CI: Confidence interval; OR: odds ratio. aChi-square test with Yates’ correction. Statistically significant p-values are shown in bold. and 143 patients with endometriosis (44). There was only one endometriosis case with GG genotype at MMP7 rs11568818. In 2008, the contribution of MMP7 rs11568818 genotype to endometriosis was examined in a Caucasian population containing 241 controls and 227 endometriosis cases. The authors found a negative association (45). In 2016, Yarmolinskaya and colleagues provided another negative finding in an extremely small cohort with only 45 controls and 78 cases (46). Thus, although Yang and colleagues analyzed Shan et al. ’s and Yarmolinskaya et al. ’s work in a meta- analysis discussing the contribution of MMP7 rs11568818 genotypes to endometriosis, the knowledge about the impacts of MMP7 genotypes on endometriosis is still controversial and far from satisfying (47). As shown in Table I, a notable finding is that the proportion of full-term pregnancy cases was significantly lower in the endometriosis group than in the control group (64.1% versus 75.9%). On the other hand, there were no significant differences observed between the two groups with regards to smoking and alcohol consumption behaviors. A previous study by Kim and colleagues reported that women with a family history of endometriosis and either smoking or early menarche had a significantly increased risk of developing endometriosis compared to the general population in Korea (55). However, due to incomplete family history records of various cancer types or endometriosis, we were unable to investigate the interaction between MMP7 rs11568818 genotypes and family history. Stratification analysis based on these factors (first full- term pregnancy, smoking, alcohol drinking, and first menarche status) did not reveal any genotypic preferences in our population (all p>0.05, data not shown). These findings are consistent with the meta-analysis conducted by Bravi and colleagues, which reported no association between tobacco smoking and endometriosis risk (56). We previously found that human 8-oxoG DNA glycosylase 1 ( hOGG1) codon 326 genotype may have a joint effect with smoking on the development of endometriosis (57). MMP7 is primarily responsible for the degradation of fibronectin, type IV collagen, laminin, nidogen, elastin, and β4-integrin (14). These extracellular matrix components are produced by various cancer cells, including breast, gastrointestinal, prostate, and endometrial tumor cells (58). MMP7 has been reported to be expressed by several types of cancer cells, such as lung (59), breast (60), head and neck (61), gastric (62), liver (63), pancreatic (64), colorectal (65) and most noticeable endometrial cancer (65). Thus, MMP7 is considered a practical marker and a potential therapeutic target for intervention. However, the role of MMP7 genotype may vary significantly among different types of cancer, and the

are still uncertain. In this study, we revealed the significant association of MMP7 genotype with endometriosis in a representative population in Taiwan for the first time. Although the genotypic findings require validation in diverse populations, the phenotypic aspects proposed by Matsuzaki and colleagues must also be examined for more detailed mechanisms. Currently, it is only suggested that the epidermal growth factor receptor–MMP7 signaling pathway may be involved in the regulation of epithelial-mesenchymal transition during endometriosis progression (66). Our results have provided an indication that MMP7 rs11568818 genotype might serve as a novel diagnosis predictor for endometriosis. More studies are urgently needed to reveal the possible critical regulation of ECM by MMPs, especially MMP7, in regard to endometriosis etiology. Conflicts of Interest The Authors declare no conflicts of interest regarding this study. Authors’ Contributions Research design: Chien HJ, Bau DT, and Tsai CW; patient and questionnaire summaries: Chien HJ, and Liu YF; experimental work: Tsai CW, Chen JC, Wang YC and Yang YC; statistical analysis: Hsieh YH, Yang YC and Tsai CW; article writing: Chang WS, Tsai CW, and Bau DT; article checking and discussion: Chien HJ, Wang YC, Chang WS, Hsieh YH, Liu YF, Yang YC, Chen JC, Bau DT and Tsai CW.

The Authors are grateful to Yu-Ting Chin and Hou-Yu Shih for their excellent technical assistance. All the participants including those who were not selected for the control group of the study are appreciated. This study was supported by Asia University and China Medical University Hospital (grant number: ASIA-112-CMUH-10) and Chung Shan Medical University and Changhua Christian Hospital, Changhua, Taiwan (CSMU-CCH-111-01). The funders had no role in study design, patient collection, experiment conduction, statistical analysis, data annotation, or decision to publish or preparation of the article.

1 Garcia Garcia JM, Vannuzzi V , Donati C, Bernacchioni C, Bruni P, Petraglia F: Endometriosis: Cellular and molecular mechanisms leading to fibrosis . Reprod Sci 30(5): 1453-1461, 2023. DOI: 10.1007/s43032-022-01083-x 2 Lamceva J, Uljanovs R, Strumfa I: The main theories on the pathogenesis of endometriosis . Int J Mol Sci 24(5): 4254, 2023. DOI: 10.3390/ijms24054254 3 Giudice LC: Clinical practice. Endometriosis. N Engl J Med 362(25): 2389-2398, 2010. DOI: 10.1056/NEJMcp1000274 4 Yang MH, Wang PH, Wang SJ, Sun WZ, Oyang YJ, Fuh JL: Women with endometriosis are more likely to suffer from migraines: a population-based study. PLoS One 7(3): e33941, 2012. DOI: 10.1371/journal.pone.0033941 5 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 Chien et al: MMP7 Genotype in Endometriosis 3055 diagnostic criteria are different: a nationwide population-based cohort study . Medicine (Baltimore) 94(39): e1633, 2015. DOI: 10.1097/MD.0000000000001633 6 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 7 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 8 Kok VC, Tsai HJ, Su CF, Lee CK: The risks for ovarian, endometrial, breast, colorectal, and other cancers in women with newly diagnosed endometriosis or adenomyosis: a population- based study. Int J Gynecol Cancer 25(6): 968-976, 2015. DOI: 10.1097/IGC.0000000000000454 9 Falconer H, D’Hooghe T, Fried G: Endometriosis and genetic polymorphisms . Obstet Gynecol Surv 62(9): 616-628, 2007. DOI: 10.1097/01.ogx.0000279293.60436.60 10 Saunders PT, Horne AW: Endometriosis: Etiology, pathobiology, and therapeutic prospects. Cell 184(11): 2807-2824, 2021. DOI: 10.1016/j.cell.2021.04.041 11 Chiorean DM, Mitranovici MI, Toru HS, Cotoi TC, Tomu ţ AN, Turdean SG, Cotoi OS: New insights into genetics of endometriosis-a comprehensive literature review . Diagnostics (Basel) 13(13): 2265, 2023. DOI: 10.3390/diagnostics13132265 12 Lekstan A, Lampe P, Lewin-Kowalik J, Olakowski M, Jablonska B, Labuzek K, Jedrzejowska-Szypulka H, Olakowska E, Gorka D, Filip I, Dranka-Bojarowska D: Concentrations and activities of metalloproteinases 2 and 9 and their inhibitors (TIMPS) in chronic pancreatitis and pancreatic adenocarcinoma. J Physiol Pharmacol 63(6): 589-599, 2012. 13 Sternlicht MD, Werb Z: How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17: 463-516, 2001. DOI: 10.1146/annurev.cellbio.17.1.463 14 Ii M, Yamamoto H, Adachi Y , Maruyama Y , Shinomura Y: Role of matrix metalloproteinase-7 (matrilysin) in human cancer invasion, apoptosis, growth, and angiogenesis. Exp Biol Med 231(1): 20-27, 2006. DOI: 10.1177/153537020623100103 15 Zuo F, Kaminski N, Eugui E, Allard J, Yakhini Z, Ben-Dor A, Lollini L, Morris D, Kim Y , DeLustro B, Sheppard D, Pardo A, Selman M, Heller RA: Gene expression analysis reveals matrilysin as a key regulator of pulmonary fibrosis in mice and humans. Proc Natl Acad Sci USA 99(9): 6292-6297, 2002. DOI: 10.1073/pnas.092134099 16 Ramankulov A, Lein M, Johannsen M, Schrader M, Miller K, Jung K: Plasma matrix metalloproteinase-7 as a metastatic marker and survival predictor in patients with renal cell carcinomas. Cancer Sci 99(6): 1188-1194, 2008. DOI: 10.1111/j.1349-7006.2008.00802.x 17 Yokoyama Y , Grünebach F, Schmidt SM, Heine A, Häntschel M, Stevanovic S, Rammensee H, Brossart P: Matrilysin(MMP-7) is a novel broadly expressed tumor antigen recognized by antigen- specific T cells. Clin Cancer Res 14(17): 5503-5511, 2008. DOI: 10.1158/1078-0432.CCR-07-4041 18 Agnihotri R, Crawford HC, Haro H, Matrisian LM, Havrda MC, Liaw L: Osteopontin, a novel substrate for matrix metalloproteinase- 3 (stromelysin-1) and matrix metalloproteinase-7 (matrilysin). J Biol Chem 276(30): 28261-28267, 2001. DOI: 10.1074/jbc.M103608200 19 Liao HY , Da CM, Liao B, Zhang HH: Roles of matrix metalloproteinase-7 (MMP-7) in cancer. Clin Biochem 92: 9-18, 2021. DOI: 10.1016/j.clinbiochem.2021.03.003 20 Piskór BM, Przylipiak A, D ąbrowska E, Niczyporuk M, Ławicki S: Matrilysins and stromelysins in pathogenesis and diagnostics of cancers . Cancer Manag Res 12: 10949-10964, 2020. DOI: 10.2147/CMAR.S235776 21 Molière S, Jaulin A, Tomasetto CL, Dali-Youcef N: Roles of matrix metalloproteinases and their natural inhibitors in metabolism: insights into health and disease . Int J Mol Sci 24(13): 10649, 2023. DOI: 10.3390/ijms241310649 22 Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM, Matrisian LM: Matrix metalloproteinase-7-dependent release of tumor necrosis factor-alpha in a model of herniated disc resorption. J Clin Invest 105(2): 143-150, 2000. DOI: 10.1172/JCI7091 23 Mitsiades N, Yu WH, Poulaki V , Tsokos M, Stamenkovic I: Matrix metalloproteinase-7-mediated cleavage of Fas ligand protects tumor cells from chemotherapeutic drug cytotoxicity. Cancer Res 61(2): 577-581, 2001. 24 McGuire JK, Li Q, Parks WC: Matrilysin (matrix metalloproteinase-7) mediates E-cadherin ectodomain shedding in injured lung epithelium. Am J Pathol 162(6): 1831-1843, 2003. DOI: 10.1016/S0002-9440(10)64318-0 25 Jung SK, Lee KW, Kim HY , Oh MH, Byun S, Lim SH, Heo YS, Kang NJ, Bode AM, Dong Z, Lee HJ: Myricetin suppresses UVB-induced wrinkle formation and MMP-9 expression by inhibiting Raf. Biochem Pharmacol 79(10): 1455-1461, 2010. DOI: 10.1016/j.bcp.2010.01.004 26 Sbardella D, Fasciglione GF, Gioia M, Ciaccio C, Tundo GR, Marini S, Coletta M: Human matrix metalloproteinases: An ubiquitarian class of enzymes involved in several pathological processes. Mol Aspects Med 33(2): 119-208, 2012. DOI: 10.1016/j.mam.2011.10.015 27 Kessenbrock K, Plaks V , Werb Z: Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141(1): 52-67, 2010. DOI: 10.1016/j.cell.2010.03.015 28 Chen L, Ke X: MMP7 as a potential biomarker of colon cancer and its prognostic value by bioinformatics analysis. Medicine (Baltimore) 100(9): e24953, 2021. DOI: 10.1097/MD.0000 000000024953 29 Liao CH, Chang WS, Hsu WL, Hu PS, Wu HC, Hsu SW, Wang BR, Yueh TC, Chen CH, Hsia TC, Huang WC, Bau DT, Tsai CW: Association of matrix metalloproteinase-7 genotypes with prostate cancer risk. Anticancer Res 43(1): 381-387, 2023. DOI: 10.21873/anticanres.16173 30 Verma SP, Das P: Monensin induces cell death by autophagy and inhibits matrix metalloproteinase 7 (MMP7) in UOK146 renal cell carcinoma cell line. In Vitro Cell Dev Biol Anim 54(10): 736-742, 2018. DOI: 10.1007/s11626-018-0298-7 31 Singh R, Mandhani A, Agrawal V , Garg M: Positive correlation between matrix metalloproteinases and epithelial-to- mesenchymal transition and its association with clinical outcome in bladder cancer patients . Cancer Microenviron 11(1): 23-39, 2018. DOI: 10.1007/s12307-017-0199-4 32 Wang WS, Chen PM, Wang HS, Liang WY , Su Y: Matrix metalloproteinase-7 increases resistance to Fas-mediated apoptosis and is a poor prognostic factor of patients with colorectal carcinoma. Carcinogenesis 27(5): 1113-1120, 2006. DOI: 10.1093/carcin/bgi351 ANTICANCER RESEARCH 44: 3051-3058 (2024) 3056 33 Vargo-Gogola T, Crawford HC, Fingleton B, Matrisian LM: Identification of novel matrix metalloproteinase-7 (matrilysin) cleavage sites in murine and human Fas ligand. Arch Biochem Biophys 408(2): 155-161, 2002. DOI: 10.1016/s0003- 9861(02)00525-8 34 Zheng HC, Sun JM, Li XH, Yang XF, Zhang YC, Xin Y: Role of PTEN and MMP-7 expression in growth, invasion, metastasis and angiogenesis of gastric carcinoma. Pathol Int 53(10): 659- 666, 2003. DOI: 10.1046/j.1440-1827.2003.01542.x 35 Knox JD, Boreham DR, Walker JA, Morrison DP, Matrisian LM, Nagle RB, Bowden GT: Mapping of the metalloproteinase gene matrilysin (MMP7) to human chromosome 11q21—>q22. Cytogenet Cell Genet 72(2-3): 179-182, 1996. DOI: 10.1159/000134181 36 Jormsjö S, Whatling C, Walter DH, Zeiher AM, Hamsten A, Eriksson P: Allele-specific regulation of matrix metalloproteinase-7 promoter activity is associated with coronary artery luminal dimensions among hypercholesterolemic patients. Arterioscler Thromb Vasc Biol 21(11): 1834-1839, 2001. DOI: 10.1161/hq1101.098229 37 Lu Z, Wang Y , Zhang Q, Zhang X, Wang S, Xie H, Li Y , Jiao B, Zhang J: Association between the functional polymorphism in the matrix metalloproteinase-7 promoter and susceptibility to adult astrocytoma. Brain Res 1118(1): 6-12, 2006. DOI: 10.1016/j.brainres.2006.08.007 38 Zhang J, Jin X, Fang S, Wang R, Li Y , Wang N, Guo W, Wang Y , Wen D, Wei L, Dong Z, Kuang G: The functional polymorphism in the matrix metalloproteinase-7 promoter increases susceptibility to esophageal squamous cell carcinoma, gastric cardiac adenocarcinoma and non-small cell lung carcinoma. Carcinogenesis 26(10): 1748-1753, 2005. DOI: 10.1093/carcin/bgi144 39 Chou AK, Hsiao CL, Shih TC, Wang HC, Tsai CW, Chang WS, Liu LC, Way TD, Chung JG, Bau DT: The contribution of matrix metalloproteinase-7 promoter genotypes in breast cancer in Taiwan. Anticancer Res 37(9): 4973-4977, 2017. DOI: 10.21873/anticanres.11908 40 Moreno-Ortiz JM, Gutiérrez-Angulo M, Partida-Pérez M, Peregrina-Sandoval J, Ramírez-Ramírez R, Muñiz-Mendoza R, Suárez-Villanueva S, Centeno-Flores M, Maciel-Gutiérrez V , Cabrales-Vazquez JE, Ayala-Madrigal ML: Association of MMP7-181A/G and MMP13-77A/G polymorphisms with colorectal cancer in a Mexican population. Genet Mol Res 13(2): 3537-3544, 2014. DOI: 10.4238/2014.February.14.1 41 Pei JS, Chou AK, Hsu PC, Tsai CW, Chang WS, Wu MF, Wu MH, Hsia TC, Cheng SP, Bau DT: Contribution of matrix metalloproteinase-7 genotypes to the risk of non-solid tumor, childhood leukemia. Anticancer Res 37(12): 6679-6684, 2017. DOI: 10.21873/anticanres.12126 42 Liao CH, Chang WS, Hu PS, Wu HC, Hsu SW, Liu YF, Liu SP, Hung HS, Bau DT, Tsai CW: The contribution of MMP-7 promoter polymorphisms in renal cell carcinoma . In Vivo 31(4): 631-635, 2017. DOI: 10.21873/invivo.11104 43 Vairaktaris E, Serefoglou Z, Yapijakis C, Vylliotis A, Nkenke E, Derka S, Vassiliou S, Avgoustidis D, Neukam FW, Patsouris E: High gene expression of matrix metalloproteinase-7 is associated with early stages of oral cancer. Anticancer Res 27(4B): 2493-2498, 2007. 44 Shan K, Lian-Fu Z, Hui D, Wei G, Na W, Xia J, Yan L: Polymorphisms in the promoter regions of the matrix metalloproteinases-7, -9 and the risk of endometriosis and adenomyosis in China. Mol Hum Reprod 12(1): 35-39, 2006. DOI: 10.1093/molehr/gal002 45 Borghese B, Chiche JD, Vernerey D, Chenot C, Mir O, Bijaoui G, Bonaiti-Pellié 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 46 Iarmolinskaia MI, Molotkov AS, Bezhenar’ VF, Shved NIu, Ivashchenko TE, Baranov VS : [ Association of matrix metalloproteinases’ polymorphisms of MMP3 and MMP9 with development of genital endometriosis]. Genetika 50(2): 230-235, 2014. 47 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 48 The American Fertility Society : Revised American Fertility Society classification of endometriosis : 1985. Fertil Steril 43(3): 351-352, 1985. 49 Chen CC, Chang WS, Pei JS, Kuo CC, Wang CH, Wang YC, Hsu PC, He JL, Gu J, Bau DT, Tsai CW: Non-homologous end- joining genotype , mRNA expression, and DNA repair capacity in childhood acute lymphocytic leukemia. Cancer Genomics Proteomics 21(2): 144-157, 2024. DOI: 10.21873/cgp.20436 50 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 51 Yueh TC, Tsao HY , Chien WC, Tsai CW, Pei JS, Wu MH, Chen CP, Chen CC, Wang ZH, Mong MC, Yang YC, Hung YC, Bau DT, Chang WS: The contribution of matrix metalloproteinase-7 promoter genotypes to hepatocellular carcinoma susceptibility. Anticancer Res 42(11): 5275-5282, 2022. DOI: 10.21873/anticanres.16034 52 Rodgers WH, Steen KG, Matrisian LM, Navre M, Giudice LC, Gorstein F: Expression and localization of matrilysin, a matrix metalloproteinase, in human endometrium during the reproductive cycle. Am J Obstet Gynecol 168(1 Pt 1) : 253-260, 1993. DOI: 10.1016/s0002-9378(12)90922-9 53 Szymanowski K, Mikołajczyk M, Wirstlein P, Dera-Szymanowska A: Matrix metalloproteinase-2 (MMP-2), MMP-9, tissue inhibitor of matrix metalloproteinases (TIMP-1) and transforming growth factor-β2 (TGF-β2) expression in eutopic endometrium of women with peritoneal endometriosis. Ann Agric Environ Med 23(4): 649- 653, 2016. DOI: 10.5604/12321966.1226861 54 Ke J, Ye J, Li M, Zhu Z: The role of matrix metalloproteinases in endometriosis: a potential target . Biomolecules 11(11): 1739, 2021. DOI: 10.3390/biom 11111739 55 Kim HJ, Lee HS, Kazmi SZ, Hann HJ, Kang T, Cha J, Choi S, Swan H, Kim H, Lee YS, Ahn HS: Familial risk for endometriosis and its interaction with smoking, age at menarche and body mass index: a population-based cohort study among siblings. BJOG 128(12): 1938-1948, 2021. DOI: 10. 1111/1471-0528.16769 56 Bravi F, Parazzini F, Cipriani S, Chiaffarino F, Ricci E, Chiantera V , Viganò P, La Vecchia C: Tobacco smoking and risk of endometriosis: a systematic review and meta-analysis. BMJ Open 4(12): e006325, 2014. DOI: 10.1136/bmjopen-2014-006325 57 Tsai CW, Ho CY , Shih LC, Ying TH, Hsieh YH, Chen YC, Chang WS, Huang CY , Pan SB, Shui HA, Chen CP, Wang PS, Bau DT: The joint effect of hOGG1 genotype and smoking habit on endometriosis in Taiwan. Chin J Physiol 56(5): 263-268, 2013. DOI: 10.4077/CJP.2013.BAB142 Chien et al: MMP7 Genotype in Endometriosis 3057 58 Shiomi T, Okada Y: MT1-MMP and MMP7 in invasion and metastasis of human cancers. Cancer Metastasis Rev 22(2-3): 145-152, 2003. DOI: 10.1023/a:1023039230052 59 Safranek J, Pesta M, Holubec L, Kulda V , Dreslerova J, Vrzalova J, Topolcan O, Pesek M, Finek J, Treska V: Expression of MMP7, MMP-9, TIMP-1 and TIMP-2 mRNA in lung tissue of patients with non-small cell lung cancer (NSCLC) and benign pulmonary disease. Anticancer Res 29(7): 2513-2517, 2009. 60 Piskór BM, Przylipiak A, D ąbrowska E, Sidorkiewicz I, Niczyporuk M, Szmitkowski M, Ławicki S: Plasma concentrations of matrilysins MMP-7 and MMP-26 as diagnostic biomarkers in breast cancer. J Clin Med 10(7): 1436, 2021. DOI: 10.3390/jcm10071436 61 Pacheco MM, Kowalski LP, Nishimoto IN, Brentani MM: Differential expression of c-jun and c-fos mRNAs in squamous cell carcinoma of the head and neck: Associations with uPA, gelatinase B, and matrilysin mRNAs. Head Neck 24(1): 24-32, 2002. DOI: 10.1002/hed.10009 62 Okayama H, Kumamoto K, Saitou K, Hayase S, Kofunato Y , Sato Y , Miyamoto K, Nakamura I, Ohki S, Sekikawa K, Takenoshita S : CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer. Oncol Rep 22(4): 745-55, 2009. DOI: 10.3892/or_00000496 63 Zeng Y , Yao X, Chen L, Yan Z, Liu J, Zhang Y , Feng T, Wu J, Liu X: Sphingosine-1-phosphate induced epithelial- mesenchymal transition of hepatocellular carcinoma via an MMP-7/ syndecan-1/TGF- β autocrine loop. Oncotarget 7(39): 63324-63337, 2016. DOI: 10.18632/oncotarget.11450 64 Jones LE, Humphreys MJ, Campbell F, Neoptolemos JP, Boyd MT: Comprehensive analysis of matrix metalloproteinase and tissue inhibitor expression in pancreatic cancer. Clin Cancer Res 10(8): 2832-2845, 2004. DOI: 10.1158/1078-0432.ccr-1157-03 65 Matsuzaki S, Maleysson E, Darcha C: Analysis of matrix metalloproteinase-7 expression in eutopic and ectopic endometrium samples from patients with different forms of endometriosis. Hum Reprod 25(3): 742-750, 2010. DOI: 10.1093/humrep/dep435 66 Chatterjee K, Jana S, DasMahapatra P, Swarnakar S: EGFR- mediated matrix metalloproteinase-7 up-regulation promotes epithelial-mesenchymal transition via ERK1-AP1 axis during ovarian endometriosis progression. FASEB J 32(8): 4560-4572, 2018. DOI: 10.1096/fj.201701382RR Received April 8, 2024 Revised May 6, 2024 Accepted May 8, 2024 ANTICANCER RESEARCH 44: 3051-3058 (2024) 3058