{"paper_id":"5125cb13-5d3d-44b4-a314-30dbbc8d97ac","body_text":"Abstract\nEndometriosis is a widespread disorder in which a tissue morphologically and physiologically similar to endometrium is observed outside the uterine cavity. Earlier, we identified a number of genes that are overexpressed in ectopic endometrium compared to eutopic endometrium. C7, FABP4, ADH1B, and PLA2G2A were the most expressed genes. The difference in their expression level was 200–300 times higher. In this work, we verified the results using real-time PCR and immunohistochemistry and examined the expression of these genes in the peritoneum of patients with endometriosis and healthy women. We have shown that a high level of expression of these genes is due to endometriotic lesions and peritoneal cells rather than eutopic endometrium. The proteins encoded by these genes (FABP4, PLA2G2A, and ADH1B) are known to be adipogenesis markers. Protein C7 is also involved in the differentiation of adipose stem cells. The equally high level of expression of these genes in endometriosis nodules and underlying peritoneum may point to a common origin of these tissues, which supports the metaplastic theory of the origin of endometriosis. In addition, our data can be interpreted as an indication that adipogenic stem cells may play a role in the pathogenesis of endometriosis. Also, our data can be interpreted as an indication of a possible involvement of adipogenic stem cells in the pathogenesis of endometriosis.\nSimilar content being viewed by others\nREFERENCES\nAnaf, V., Simon, P., Fayt, I., and Noel, J., Smooth muscles are frequent components of endometriotic lesions, Hum. Reprod., 2000, vol. 15, pp. 767–771.\nAntonio, V., Brouillet, A., Janvier, B., Monne, C., Bereziat, G., Andreani, M., and Rayondjean, M., Transcriptional regulation of the rat type IIA phospholipase A2 gene by cAMP and interleukin-1beta in vascular smooth muscle cells: interplay of the CCAAT/enhancer binding protein (C/EBP), nuclear factor-kappaB and Ets transcription factors, Biochem. J., 2002, vol. 368, pp. 415–424.\nBackonja, U., Buck Louis, G.M., and Lauver, D.R., Overall adiposity, adipose tissue distribution, and endometriosis: a systematic review, Nurs. Res., 2016, vol. 65, pp. 151–166.\nBackonja, U., Hediger, M.L., Chen, Z., Lauver, D.R., Sun, L., Peterson, C.M., and Buck Louis, G.M., Beyond body mass index: using anthropometric measures and body composition indicators to assess odds of an endometriosis diagnosis, J. Womens Health, 2017, vol. 26, pp. 941–950.\nBiron-Shental, T., Schaiff, W.T., Ratajczak, C.K., Bildirici, I., Nelson, D.M., and Sadovsky, Y., Hypoxia regulates the expression of fatty acid-binding proteins in primary term human trophoblasts, Am. J. Obstet. Gynecol., 2007, vol. 197, p. 516. e1–6. https://doi.org/10.1016/j.ajog.2007.03.066\nBossi, F., Rizzi, L., Bulla, R., Debeus, A., Tripodo, C., Picotti, P., Betto, E., Macor, P., Pucillo, C., Würzner, R., and Tedesco, F., C7 is expressed on endothelial cells as a trap for the assembling terminal complement complex and may exert anti-inflammatory function, Blood, 2009, vol. 113, pp. 3640–3648.\nDe Joliniere, J.B., Ayoubi, J.M., Lesec, G., Validire, P., Goguin, A., Gianaroli, L., Dubuisson, J.B., Feki, A., and Gogusev, J., Identification of displaced endometrial glands and embryonic duct remnants in female fetal reproductive tract: possible pathogenetic role in endometriotic and pelvic neoplastic processes, Front. Physiol., 2012, vol. 3.https://doi.org/10.3389/fphys.2012.00444\nElmasri H., Karaaslan, C., Teper, Y., Ghelfi, E., Weng, M., Ince, T.A., Kozakewich, H., Bischoff, J., and Cataltepe, S., Fatty acid binding protein 4 is a target of VEGF and a regulator of cell proliferation in endothelial cells, FASEB J., 2009, vol. 23, pp. 3865–3873.\nEyster, K.M., Klinkova, O., Kennedy, V., and Hansen, K.A., Whole genome deoxyribonucleic acid microarray analysis of gene expression in ectopic versus eutopic endometrium, Fertil. Steril., 2007, vol. 88, pp. 1505–1533.\nFischer, H., Gustafsson, T., Sundberg, C.J., Norrbom, J., Ekman, M., Johansson, O., and Jansson, E., Fatty acid binding protein 4 in human skeletal muscle, Biochem. Biophys. Res. Commun., 2006, vol. 346, pp. 125–130.\nGirona, J., Rosales, R., Plana, N., Saavedra, P., Masana, L., and Vallvé, J.C., FABP4 induces vascular smooth muscle cell proliferation and migration through a MAPK-dependent pathway, PLoS One, 2013, vol. 8. e81914. https://doi.org/10.1371/journal.pone.0081914\nGruenwald, P., Origin of endometriosis from the mesenchyme of the celomic walls, Am. J. Obstetrics Gynecol., 1942, vol. 44, pp. 470–474.\nHawksworth, O.A., Coulthard, L.G., Mantovani, S., and Woodruff, T.M., Complement in stem cells and development, Semin. Immunol., 2018, vol. 37, pp. 74–84.\nHawksworth, O.A., Coulthard, L.G., and Woodruff, T.M., Complement in the fundamental processes of the cell, Mol. Immunol., 2017, vol. 84, pp. 17–25.\nKocbek, V., Bersinger, N.A., Brglez, V., Mueller, M.D., Petan, T., and Rižner, T.L., Phospholipase A2 group IIA is elevated in endometriomas but not in peritoneal fluid and serum of ovarian endometriosis patients, Gynecol. Endocrinol., 2015, vol. 31, pp. 214–218.\nKralisch, S. and Fasshauer, M., Adipocyte fatty acid binding protein: a novel adipokine involved in the pathogenesis of metabolic and vascular disease?, Diabetologia, 2013, vol. 56, pp. 10–21.\nKuefner, M.S., Pham, K., Redd, J.R., Stephenson, E.J., Harvey, I., Deng, X., Bridges, D., Boilard, E., Elam, M.B., and Park, E.A., Secretory phospholipase A2 group IIA modulates insulin sensitivity and metabolism, J. Lipid. Res., 2017, vol. 58, pp. 1822–1833.\nKunju, L.P., Cookingham, C., Toy, K.A., Chen, W., Sabel, M.S., and Kleer, C.G., EZH2 and ALDH-1 mark breast epithelium at risk for breast cancer development, Mod. Pathol., 2011, vol. 24, pp. 786–793.\nKugiyama, K., Ota, Y., Takazoe, K., Moriyama, Y., Kawano, H., Miyao, Y., Sakamoto, T., Soejima, H., Ogawa, H., Doi, H., Sugiyama, S., and Yasue, H., Circulating levels of secretory type II phospholipase A(2) predict coronary events in patients with coronary artery disease, Circulation, 1999, vol. 100, pp. 1280–1284.\nLaganà, A.S., Sturlese, E., Retto, G., Sofo, V., and Triolo, O., Interplay between misplaced Müllerian-derived stem cells and peritoneal immune dysregulation in the pathogenesis of endometriosis, Obstet. Gynecol., 2013, article ID 527041. https://doi.org/10.1155/2013/527041\nLaganà, A.S., Vitale, S.G., Salmeri, F.M., Triolo, O., Ban, Frangež, H., Vrtačnik-Bokal, E., Stojanovska, L., Apostolopoulos, V., Granese, R., and Sofo, V., Unus pro omnibus, omnes pro uno: a novel, evidence-based, unifying theory for the pathogenesis of endometriosis, Med. Hypotheses, 2017, vol. 103, pp. 10–20.\nLamounier-Zepter, V., Look, C., Alvarez, J., Christ, T., Ravens, U., Schunck, W.H., Ehrhart-Bornstein, M., Bornstein, S.R., and Morano, I., Adipocyte fatty acid-binding protein suppresses cardiomyocyte contraction: a new link between obesity and heart disease, Circ. Res., 2009, vol. 105, pp. 326–334.\nLayne, M.D., Patel, A., Chen, Y.H., Rebel, V.I., Carvajal, I.M., Pellacani, A., Ith, B., Zhao, D., Schreiber, B.M., Yet, S.F., Lee, M.E., Storch, J., and Perrella, M.A., Role of macrophage-expressed adipocyte fatty acid binding protein in the development of accelerated atherosclerosis in hypercholesterolemic mice, FASEB J., 2001, vol. 15, pp. 2733–2735.\nLivak, K.J. and Schmittgen, T.D., Analysis of relative gene expression data using real-time quantitative PCR and the 2(–Delta Delta C(T)) method, Methods, 2001, vol. 25, pp. 402–408.\nLousse, J.C., Defrère, S., Colette, S., Van Langendonckt, A., and Donnez, J., Expression of eicosanoid biosynthetic and catabolic enzymes in peritoneal endometriosis, Hum. Reprod., 2010, vol. 25, pp. 734–741.\nMakowski, L., Boord, J.B., Maeda, K., Babaev, V.R., Uysal, K.T., Morgan, M.A., Parker, R.A., Suttles, J., Fazio, S., Hotamisligil, G.S., and Linton, M.F., Lack of macrophage fatty-acid-binding protein aP2 protects mice deficient in apolipoprotein E against atherosclerosis, Nat. Med., 2001, vol. 7, pp. 699–705.\nPredeus, A.V., Vashukova, E.S., Glotov, A.S., Danilova, M.M., Osinovskaya, N.S., Malysheva, O.V., Shved, N.Yu., Ganbarli, N., Yarmolinskaya, M.I., Ivashchenko, T.E., and Baranov, V.S., Next-generation sequencing of matched ectopic and eutopic endometrium identifies novel endometriosis-related genes, Russ. J. Genet., 2018, vol. 54, pp. 1358–1365.\nRaimondo, D., Mabrouk, M., Zannoni, L., Arena, A., Zanello, M., Benfenati, A., Moro, E., Paradisi, R., and Seracchioli, R., Severe ureteral endometriosis: frequency and risk factors, J. Obstet. Gynaecol., 2018, vol. 38, pp. 257–260.\nRedwine, D.B., Was Sampson wrong?, Fertil. Steril., 2002, vol. 78, pp. 686–693.\nRidley, J.H., The histogenesis of endometriosis, Obstet. Gynecol. Survey, 1968, vol. 23, pp. 1–35.\nSaare, M., Rekker, K., Laisk-Podar, T., Sõritsa, D., Roost, A.M., Simm, J., Velthut-Meikas, A., Samuel, K., Metsalu, T., Karro, H., Sõritsa, A., Salumets, A., and Peters, M., High-throughput sequencing approach uncovers the miRNome of peritoneal endometriotic lesions and adjacent healthy tissues, PLoS One, 2014, vol. 9. e112630. https://doi.org/10.1371/journal.pone.0112630\nSampson J.A., Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation, Am. J. Pathol., 1927, vol. 3, pp. 93–110.\nSeol, H.S., Lee, S.E., Song, J.S., Rhee, J.K., Singh, S.R., Chang, S., and Jang, S.J., Complement proteins C7 and CFH control the stemness of liver cancer cells via LSF-1, Cancer Lett., 2016, vol. 372, pp. 24–35.\nShah, D.K., Correia, K.F., Vitonis, A.F., and Missmer, S.A., Body size and endometriosis: results from 20 years of follow-up within the Nurses’ Health Study II prospective cohort, Hum. Reprod., 2013, vol. 28, pp. 1783–1792.\nShum, B.O., Mackay, C.R., Gorgun, C.Z., Frost, M.J., Kumar, R.K., Hotamisligil, G.S., and Rolph, M.S., The adipocyte fatty acid-binding protein aP2 is required in allergic airway inflammation, J. Clin. Invest., 2006, vol. 116, pp. 2183–2192.\nSuryawanshi, S., Huang, X., Elishaev, E., Budiu, R.A., Zhang, L., Kim, S., Donnellan, N., Mantia-Smaldone, G., Ma, T., Tseng, G., Lee, T., Mansuria, S., Edwards, R.P., and Vlad, A.M., Complement pathway is frequently altered in endometriosis and endometriosis-associated ovarian cancer, Clin. Cancer Res., 2014, vol. 20, pp. 6163–6174.\nTews, D., Schwar, V., Scheithauer, M., Weber, T., Fromme, T., Klingenspor, M., Barth, T.F., Möller, P., Holzmann, K., Debatin, K.M., Fischer-Posovszky, P., and Wabitsch, M., Comparative gene array analysis of progenitor cells from human paired deep neck and subcutaneous adipose tissue, Mol. Cell Endocrinol., 2014, vol. 395, pp. 41–50.\nThompson, K.J., Austin, R.G., Nazari, S.S., Gersin, K.S., Iannitti, D.A., and McKillop, I.H., Altered fatty acid-binding protein 4 (FABP4) expression and function in human and animal models of hepatocellular carcinoma, Liver Int., 2018, vol. 38, pp. 1074–1083.\nTian, Z., Zhao, Z.A., Liang, X.H., Zhang, X.H., Sha, A.G., Zhang, Z.R., Yu, Y.S., and Yang, Z.M., Expression and function of fatty acid-binding protein 4 during mouse decidualization, Fertil. Steril., 2011, vol. 95, pp. 2749–2752.\nZafrakas, M., Tarlatzis, B.C., Streichert, T., Pournaropoulos, F., Wölfle, U., Smeets, S.J., Wittek, B., Grimbizis, G., Brakenhoff, R.H., Pantel, K., Bontis, J., and Günes, C., Genome-wide microarray gene expression, array-CGH analysis, and telomerase activity in advanced ovarian endometriosis: a high degree of differentiation rather than malignant potential, Int. J. Mol. Med., 2008, vol. 21, pp. 335–344.\nZhu, Q., Jin, Y., Wang, P., Wang, H., Lu, B., Wang, Z., and Dong, M., Expression and function of fatty acid-binding protein 4 in epithelial cell of uterine endometrium, Cell Biol. Int., 2015, vol. 39, no. 5, pp. 540–547.\nZimmerman, A.W. and Veerkamp, J.H., New insights into the structure and function of fatty acid-binding proteins, Cell. Mol. Life Sci., 2002, vol. 59, pp. 1096–1116.\nYang, Y., Luo, J., Yu, D., Zhang, T., Lin, Q., Li, Q., Wu, X., Su, Z., Zhang, Q., Xiang, Q., and Huang, Y., Vitamin A promotes Leydig cell differentiation via alcohol dehydrogenase 1, Front. Endocrinol., 2018, vol. 9, p. 644. https://doi.org/10.3389/fendo.2018.00644\nYarmolinskaya, M.I. and Ailamazyan, E.K., Genital’nyi endometrioz. Razlichnye grani problemy (Genital Endometriosis: Various Facets of the Problem), St. Petersburg: Eko-Vektor, 2017.\nYing, L., Zhang, F., Pan, X., Chen, K., Zhang, N., Jin, J., Wu, J., Feng, J., Yu, H., Jin, H., and Su, D., Complement component 7 (C7), a potential tumor suppressor, is correlated with tumor progression and prognosis, Oncotarget, 2016, vol. 7, pp. 86536–86546.\nFunding\nThis work was supported by the Russian Science Foundation, project no. 19-15-00108.\nAuthor information\nAuthors and Affiliations\nCorresponding author\nEthics declarations\nConflict of interest. The authors declare that they have no conflict of interest.\nStatement of compliance with standards of research involving humans as subjects. All procedures performed with the participation of people complied with the ethical standards of the institutional and/or national research ethics committee and the Helsinki Declaration (1964) and its subsequent changes or comparable to ethical standards. Informed consent was obtained from each participant. The work was approved by the Ethics Committee of the Ott Research Institute of Obstetrics, Gynecology, and Reproductology,\nAdditional information\nTranslated by I. Fridlyanskaya\nAbbreviations: IHC—immunohistochemistry, EGE—external genital endometriosis, RT-PCR—reverse transcription polymerase chain reaction, EH—endometrioid heterotopias, FDR—false discovery rate, average proportion of false hypotheses.\nRights and permissions\nAbout this article\nCite this article\nMalysheva, O.V., Kopteva, O.S., Krylova, Y.S. et al. Expression of Protein Markers of Adipogenesis in Endometriotic Lesions. Cell Tiss. Biol. 14, 129–138 (2020). https://doi.org/10.1134/S1990519X20020066\nReceived:\nRevised:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1134/S1990519X20020066","source_license":"CC0","license_restricted":false}