Matrix metalloproteinase-11 as a potential tumor marker of uterine leiomyoma
Kuznetsova M.V., Pozdnyakova N.V., Bykova D.V., Karyagina V.Ye., Tonoyan N.M., Trubnikova E.V.
Objective. To evaluate the specific activity of serum immunoglobulins against the matrix metalloproteinase-11 (MMP11) protein in the groups of mothers of many children and patients with uterine fibroids.
Materials and methods. A cDNA fragment containing the MMP11 gene from a cell line with increased expression of this protein was cloned. Recombinant human MMP11 protein produced in E. coli was purified and used to investigate the limit titer of antibodies in blood sera of patients using indirect ELISA. Donor blood serum samples (100 samples) were collected from the patients undergoing treatment at V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology. Informed consent to participate in the study was obtained from the patients. To investigate the immunological activity of sera against the MMP11 protein, four groups of patients were formed. Group 1 consisted of women without diagnosed fibroids who had a history of five or more successful pregnancies. Group 2 consisted of women with fibroids, who also had five or more successful pregnancies. Group 3 included women with recurrent fibroids. Group 4 was the control group of men. An expression construct containing the MMP11 gene was inserted into the E. coli genome. As a result, preparative protein was obtained in sufficient amount to investigate its reaction with antibodies in the blood sera of different patient groups.
Results. Western blot analysis showed that the blood sera of women without fibroids, who had many children, contain antibodies to the MMP11 protein, that provided grounds for a broader study of the immunological reactivity of the blood sera in different groups of patients against this protein. In gentral, the highest protein reactivity was shown in the sera of women with many children. However, the average value for the group of women with fibroids, who had many childeren, was higher, but not statistically significant. In patients with fibroids the reactivity was lower than in group 1, and the lowest was in the control group of men. At the same time, statistical analysis showed significant differences between the groups using different dilutions, that is, there was a dose dependence of the immunological response. The obtained results confirm statistically significant differences in serum reactivity between the studied groups. At the same time, the identified dose-dependent dynamics corresponds to the expected immunological patterns.
Conclusion. Our study showed that the MMP11 protein reacts with antibodies from the sera of different patient groups. At the same time, higher immune response to this protein was found in the group of mothers with many children. The MMP11 protein may further be useful in the development and testing of new targeted preventive therapy for uterine fibroids.
Authors' contributions. Kuznetsova M.V. – literature review, the study concept and design; Pozdnyakova N.V. – protein cloning; Karyagina V.Ye. – protein identification, Western blot analysis; Tonoyan N.S. – biomaterial collection; Bykova D.V. – performance of indirect enzyme-linked immunosorbent assay; Trubnikova E.V. – statistical data processing; Kuznetsova M.V., Trubnikova E.V. – manuscript writing and editing.
Conflicts of interest. The authors confirm that they have no conflict of interest to declare.
Funding. Project No. 23-15-00069 of the Russian Science Foundation “The development of a prophylactic vaccine to prevent the development of uterine leiomyoma in patients planning pregnancy”.
Ethical Approval. The study was approved by the Biomedical Research Ethics Committee at V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia (Protocol of May 23, 2024).
Generative Artificial Intelligence. No generative AI tools was used in preparing this article.
Patient Consent for Publication. All patients have signed informed consent for publication of the obtained data.
Authors' Data Sharing Statement. The data supporting the findings of this study are available on request from the corresponding author after approval from the principal investigator.
For citation: Kuznetsova M.V., Pozdnyakova N.V., Bykova D.V., Karyagina, V.Ye., Tonoyan N.M.,
Trubnikova E.V. Matrix metalloproteinase-11 as a potential tumor marker of uterine leiomyoma.
Akusherstvo i Ginekologiya/Obstetrics and Gynecology. 2026; (6): 125-134 (in Russian)
https://dx.doi.org/10.18565/aig.2025.322
Keywords
uterine fibroids
gene expression
MMP11
References
- Миома матки. Клинические рекомендации. Акушерство и гинекология. 2025; 8 (Приложение). https://dx.doi.org/10.18565/aig.2025.234 [Uterine fibroids. Clinical guidelines. Obstetrics and Gynecology. 2025; 8 (Suppl.) (in Russian). https://dx.doi.org/10.18565/aig.2025.234].
- Pavone D., Clemenza S., Sorbi F., Fambrini M., Petraglia F. Epidemiology and risk factors of uterine fibroids. Best Pract. Res. Clin. Obstet. Gynaecol. 2018; 46: 3-11. https://dx.doi.org/10.1016/j.bpobgyn.2017.09.004
- Уварова Е.В., Адамян Л.В., Стрижакова М.А. и др. Рецидивирующая миома матки у юной пациентки (клиническое наблюдение). Репродуктивное здоровье детей и подростков. 2005; 1: 53-7. [Uvarova E.V., Adamyan L.V., Strizhakova M.A. et al. Recurrent uterine fibroids in a young patient (clinical observation). Reproductive Health of Children and Adolescents. 2005; 1:53-7 (in Russian)].
- Maekawa R., Sato S., Tamehisa T., Sakai T., Kajimura T., Sueoka K., Sugino N. Different DNA methylome, transcriptome and histological features in uterine fibroids with and without MED12 mutations. Sci. Rep. 2022; 12(1): 8912. https://dx.doi.org/10.21203/rs.3.rs-1041773/v1
- Navarro A., Yin P., Monsivais D., Lin S.M., Du P., Wei J.J. et al. Genome-wide DNA methylation indicates silencing of tumor suppressor genes in uterine leiomyoma. PLoS One. 2012; 7(3): e33284. https://dx.doi.org/10.1371/journal.pone.0033284
- Andreini C., Bertini I., Cavallaro G., Holliday G.L., Thornton J.M. Metal ions in biological catalysis: from enzyme databases to general principles. JBIC J. Biol. Inorg. Chem. 2008; 13(8): 1205-18. https://dx.doi.org/10.1007/s00775-008-0404-5
- Lefebvre O., Régnier C., Chenard M.P., Wendling C., Chambon P., Basset P. et al. Developmental expression of mouse stromelysin-3 mRNA. Development. 1995; 121(4): 947-55. https://dx.doi.org/10.1242/dev.121.4.947
- Okada A., Saez S., Misumi Y., Basset P. Rat stromelysin 3: cDNA cloning from healing skin wound, activation by furin and expression in rat tissues. Gene. 1997; 185(2): 187-93. https://dx.doi.org/10.1016/S0378-1119(96)00615-4
- Wang Z., Brown D.D. Thyroid hormone-induced gene expression program for amphibian tail resorption. J. Biol. Chem. 1993; 268(22): 16270-8.
- Basset P., Bellocq J.P., Wolf C., Stoll I., Hutin P., Limacher J.M. et al. A novel metalloproteinase gene specifically expressed in stromal cells of breast carcinomas. Nature. 1990; 348(6303): 699-704. https://dx.doi.org/10.1038/348699a0
- Chen C., Liu X., Jiang J., Li S., Wang G., Ju L. et al. Matrix metalloproteinase 11 is a potential biomarker in bladder cancer diagnosis and prognosis. Onco Targets Ther. 2020; 13: 9059-69. https://dx.doi.org/10.2147/OTT.S243452
- Panara K., Hui T.L., Keshari D., Tong C.C.L., Palmer J.N., Adappa N.D. et al. Matrix metalloproteinase-11 regulates inverted papilloma epithelial cell migration and invasion. Int. Forum Allergy Rhinol. 2024; 14(11): 1714-23. https://dx.doi.org/10.1002/alr.23405
- Denys H., De Wever O., Nusgens B., Kong Y., Sciot R., Le A.T. et al. Invasion and MMP expression profile in desmoid tumours. Br. J. Cancer. 2004; 90(7): 1443-9. https://dx.doi.org/10.1038/sj.bjc.6601661
- Yoon M.L., Kim S.Y., Chun H., Park J., Seo W.J., Lee J.Y. et al. Diagnostic accuracy of serum biomarkers MMP11 and SPP1 in non-small cell lung cancer: an analysis of sensitivity, specificity, and area under the curve. Transl. Lung Cancer Res. 2025; 14(4): 1197-211. https://dx.doi.org/10.21037/tlcr-2024-1068
- Xu W., Liang T., Fang H., Fu L., Deng D., Tan X. et al. Single-cell RNA Sequencing identifies MMP11+cancer-associated fibroblasts as drivers of angiogenesis and bladder cancer progression. Adv. Sci. (Weinh). 2025; 12(32): e02774. https://dx.doi.org/10.1002/advs.202502774
- von Marschall Z., Riecken E.O., Rosewicz S. Stromelysin 3 is overexpressed in human pancreatic carcinoma and regulated by retinoic acid in pancreatic carcinoma cell lines. Gut. 1998; 43(5): 692-8. https://dx.doi.org/10.1136/gut.43.5.692
- Perret A.G., Duthel R., Fotso M.J., Brunon J., Mosnier J.F. Stromelysin-3 is expressed by aggressive meningiomas. Cancer. 2002; 94(3): 765-72. https://dx.doi.org/10.1002/cncr.10270
- Xu J., Fang Y., Chen K., Li S., Tang S., Ren Y. et al. Single-cell RNA sequencing reveals the tissue architecture in human high-grade serous ovarian cancer. Clin. Cancer Res. 2022; 28(16): 3590-602. https://dx.doi.org/10.1158/1078-0432.CCR-22-0296
- Chu J., Wang D., Guo F., Li D., Li Z., Ding H. et al. Expression and clinical significance of FOXQ1, MMP11, and CST1 in colorectal cancer. Clin. Lab. 2026; 72(2). https://dx.doi.org/10.7754/Clin.Lab.2025.250764
- Акуленко Л.В., Нерсесян Е.А., Кузнецова М.В., Адамян Л.В. Профилирование дифференциальной экспрессии генов в миоматозных узлах и миометрии при первичной и рецидивной миоме матки. Медицинская генетика. 2025; 24(8): 29-31. https://dx.doi.org/10.25557/2073-7998.2025.08.29-31 [Akulenko L.V., Nersesyan E.A., Kuznetsova M.V., Adamyan L.V. Profiling of differential gene expression in leomyoma and myometrium in primary and recurrent uterine fibroids. Medical Genetics. 2025; 24(8): 29-31 (in Russian) https://dx.doi.org/10.25557/2073-7998.2025.08.29-31].
- Кузнецова М.В., Трофимов Д.Ю., Тихончук Е.Ю., Согоян Н.С., Адамян Л.В., Сухих Г.Т. Молекулярные механизмы патогенеза миомы матки: анализ мутаций гена MED12 в российской популяции. Акушерство и гинекология. 2016; 10: 73-9. https://dx.doi.org/10.18565/aig.2016.10.73-9 [Kuznetsova M.V., Trofimov D.Yu., Tikhonchuk E.Yu., Sogoyan N.S., Adamyan L.V., Sukhikh G.T. Molecular mechanisms of uterine fibroids pathogenesis: analysis of MED12 gene mutations in the Russian population. Obstetrics and Gynecology. 2016; (10): 73-9 (in Russian). http://dx.doi.org/10.18565/aig.2016.10.73-9].
- Kuznetsova M.V., Tonoyan N.M., Trubnikova E.V., Zelensky D.V., Svirepova K.A., Adamyan L.V. et al. Novel approaches to possible targeted therapies and prophylaxis of uterine fibroids. Diseases. 2023; 11(4): 156. https://dx.doi.org/10.3390/diseases11040156
- Peruzzi D., Mori F., Conforti A., Lazzaro D., De Rinaldis E., Ciliberto G. et al. MMP11: a novel target antigen for cancer immunotherapy. Clin. Cancer Res. 2009; 15(12): 4104-13.
- Umezawa K., Lin Y. Inhibition of matrix metalloproteinase expression and cellular invasion by NF-κB inhibitors of microbial origin. Biochim. Biophys. Acta Proteins Proteom. 2020; 1868(6): 140412. https://dx.doi.org/10.1016/j.bbapap.2020.140412
- Kou Y.B., Zhang S.Y., Zhao B.L., Ding R., Liu H., Li S. Knockdown of MMP11 inhibits proliferation and invasion of gastric cancer cells. Int. J. Immunopathol. Pharmacol. 2013; 26(2): 361-70. https://dx.doi.org/10.1177/039463201302600209
- Goad J., Rajkovic A. Uterine fibroids at single-cell resolution: unveiling cellular heterogeneity to improve understanding of pathogenesis and guide future therapies. Am. J. Obstet. Gynecol. 2025; 232(4S): S124-34. https://dx.doi.org/10.1016/j.ajog.2024.08.037
- Wang Z., Guo X., Li X., Wang J., Zhang N., Amin B. et al. Cancer-associated fibroblast-derived MMP11 promotes tumor progression in pancreatic cancer. Cancer Sci. 2025; 116(3): 643-55. https://dx.doi.org/10.1111/cas.16418
Received 07.11.2025
Accepted 09.06.2026
About the Authors
Maria V. Kuznetsova, PhD, Senior Researcher at the Laboratory of Molecular Genetic Methods, Institute of Reproductive Genetics, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4 Oparina str., Moscow, 117997, Russia, mkarja@mail.ru,https://orcid.org/0000-0003-3790-0427
Natalia V. Pozdniakova, PhD, Senior Researcher at the Laboratory of Radionuclide and Radiation Technologies in Experimental Oncology, Blokhin National Research Medical Center, Ministry of Health of Russia, 23 Kashirskoe Shosse, Moscow, 115230, Russia, +7(977)767-99-90, natpo2002@mail.ru, https://orcid.org/0000-0002-5765-3016
Daria V. Bykova, Researcher at the Central Pathoanatomical Laboratory, Research Institute of Human Morphology, 3 Tsyurupy str., Moscow, 117418, Russia,
+7(916)594-89-06, dashasam@mail.ru, https://orcid.org/0000-0001-5639-0835
Viktoria E. Karyagina, PhD, Senior Researcher at the Institute of Translation Medicine, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia, 4 Oparina str., Moscow, 117997, Russia, vypryazhkina.viktoriya@mail.ru
Narine M. Tonoyan, PhD, Doctor, V.I. Kulakov National Medical Research Center for Obstetrics, Gynecology and Perinatology, Ministry of Health of Russia,
4 Oparina str., Moscow, 117997, Russia, tonnar.13@bk.ru, SPIN: 8547-9399, Scopus Author ID: 57213609878, https://orcid.org/0000-0002-1631-1829
Elena V. Trubnikova, Dr. Bio. Sci., Associate Professor, Chief Researcher at the Research Institute of Genetics, Kursk State University, 33 Radishcheva str., Kursk, 305000, Russia; Leading Researcher, Vavilov Institute of General Genetics of the Russian Academy of Sciences, 3 Gubkina str., GSP-1, Moscow, 119991, Russia, +7(910)311-18-86, tr_e@list.ru, https://orcid.org/0000-0001-5025-9406
Corresponding author: Maria V. Kuznetsova, mkarja@mail.ru
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