{"paper_id":"2e0ffa6d-c738-4ef5-b114-b10743e58f75","body_text":"Abstract\nEndometriosis is a chronic gynecological disease in women of childbearing age, which leads to infertility with risk of endometrial and ovarian cancer. The pathogenesis of endometriosis is poorly understood, and cure/treatment for it is not available, except for symptomatic treatment. The recurrence rate of endometriosis is high. SLP-2 is an inner mitochondrial membrane protein whose participation has been explained in cases of endometrial stromal cell growth, differentiation and migration, but its role in endometriosis is yet to be understood. Previous studies have found altered expression of stomatin-like protein 2 (SLP-2) in the serum of endometriotic patients. Therefore, we have studied the possible role of SLP-2 in the development of endometriosis. We found the ubiquitous and high expression of SLP-2 in the endometriotic tissue of both human endometriosis patients and rat endometriosis model. SLP-2 is seen in the glandular epithelial cells and stromal cells in the eutopic/normal or non-endometriosis group endometrium from human subjects. Finding high expression levels of SLP-2 in endometriotic tissue and ovarian cystic cells derived from endometriosis patients, we explored the possible role of SLP-2 in the cell aggregation, colonization, migration, and invasion in the human endometriotic cells associated with the progression of the endometriosis. Transient silencing of SLP-2 by its siRNA hinders endometriotic cells, aggregation, migration, and invasion into the extracellular matrix, which confirms SLP-2 involvement in endometriotic disease onset and progression. This study unravels the ubiquitous expression of SLP-2 in the human ectopic endometrial tissue and its role in the endometriotic cell migration, colonization, aggregation, and invasion leading to endometriosis progression.\nSimilar content being viewed by others\nData Availability\nThe authors declare availability of the data and materials.\nCode Availability\nNot applicable.\nReferences\nAbrao MS, Petraglia F, Falcone T, Keckstein J, Osuga Y, Chapron C. Deep endometriosis infiltrating the recto-sigmoid: critical factors to consider before management. Hum Reprod Updat. 2015;21:329–39.\nBulun SE, Yilmaz BD, Sison C, Miyazaki K, Bernardi L, Liu S, Kohlmeier A, Yin P, Milad M, Wei J. Endometriosis. Endocr Rev. 2019;40:1048–79.\nChadchan SB, Kumar V, Maurya VK, Soni UK, Jha RK. Endoglin (CD105) coordinates the process of endometrial receptivity for embryo implantation. Mol Cell Endocrinol. 2016;425:69–83.\nChristie DA, Lemke CD, Elias IM, Chau LA, Kirchhof MG, Li B, Ball EH, Dunn SD, Hatch GM, Madrenas J. Stomatin-like protein 2 binds cardiolipin and regulates mitochondrial biogenesis and function. Mol Cell Biol. 2011;31:3845–56.\nDuffy JM, Arambage K, Correa FJ, Olive D, Farquhar C, Garry R, Barlow DH, Jacobson TZ. Laparoscopic surgery for endometriosis. Cochrane Database Syst Rev. 2014;CD011031.\nDunselman GA, Vermeulen N, Becker C, Calhaz-Jorge C, D’Hooghe T, De Bie B, Heikinheimo O, Horne AW, Kiesel L, Nap A, et al. ESHRE guideline: management of women with endometriosis. Hum Reprod. 2014;29:400–12.\nFuldeore M, Chwalisz K, Marx S, Wu N, Boulanger L, Ma L, Lamothe K. Surgical procedures and their cost estimates among women with newly diagnosed endometriosis: a US database study. J Med Econ. 2011;14:115–23.\nGajbhiye R, Bendigeri T, Ghuge A, Bhusane K, Begum S, Warty N, Sawant R, Padte K, Humane A, Dasmahapatra P, et al. Panel of autoimmune markers for noninvasive diagnosis of minimal-mild endometriosis. Reprod Sci. 2017;24:413–20.\nGajbhiye R, Sonawani A, Khan S, Suryawanshi A, Kadam S, Warty N, Raut V, Khole V. Identification and validation of novel serum markers for early diagnosis of endometriosis. Hum Reprod. 2012;27:408–17.\nGiudice LC, Kao LC. Endometriosis Lancet. 2004;364:1789–99.\nKobayashi H, Higashiura Y, Shigetomi H, Kajihara H. Pathogenesis of endometriosis: the role of initial infection and subsequent sterile inflammation (Review). Mol Med Rep. 2014;9:9–15.\nKumar V, Maurya VK, Joshi A, Meeran SM, Jha RK. Integrin beta 8 (ITGB8) regulates embryo implantation potentially via controlling the activity of TGF-B1 in mice. Biol Reprod. 2015;92:109.\nLaschke MW, Korbel C, Rudzitis-Auth J, Gashaw I, Reinhardt M, Hauff P, Zollner TM, Menger MD. High-resolution ultrasound imaging: a novel technique for the noninvasive in vivo analysis of endometriotic lesion and cyst formation in small animal models. Am J Pathol. 2010;176:585–93.\nMachado DE, Berardo PT, Palmero CY, Nasciutti LE. Higher expression of vascular endothelial growth factor (VEGF) and its receptor VEGFR-2 (Flk-1) and metalloproteinase-9 (MMP-9) in a rat model of peritoneal endometriosis is similar to cancer diseases. J Exp Clin Cancer Res. 2010;29:4.\nRogers PA, D’Hooghe TM, Fazleabas A, Gargett CE, Giudice LC, Montgomery GW, Rombauts L, Salamonsen LA, Zondervan KT. Priorities for endometriosis research: recommendations from an international consensus workshop. Reprod Sci. 2009;16:335–46.\nRudzitis-Auth J, Korbel C, Scheuer C, Menger MD, Laschke MW. Xanthohumol inhibits growth and vascularization of developing endometriotic lesions. Hum Reprod. 2012;27:1735–44.\nShaw RW. Treatment of endometriosis. Lancet. 1992;340:1267–71.\nSoni UK, Chadchan SB, Joshi A, Kumar V, Maurya VK, Verma RK, Jha RK. Poly(ADP-ribose) polymerase-2 is essential for endometrial receptivity and blastocyst implantation, and regulated by caspase-8. Mol Cell Endocrinol. 2020;518:110946.\nSoni UK, Chadchan SB, Kumar V, Ubba V, Khan MTA, Vinod BSV, Konwar R, Bora HK, Rath SK, Sharma S, et al. A high level of TGF-B1 promotes endometriosis development via cell migration, adhesiveness, colonization, and invasivenessdagger. Biol Reprod. 2019;100:917–38.\nTondera D, Grandemange S, Jourdain A, Karbowski M, Mattenberger Y, Herzig S, Da Cruz S, Clerc P, Raschke I, Merkwirth C, et al. SLP-2 is required for stress-induced mitochondrial hyperfusion. EMBO J. 2009;28:1589–600.\nTurgut M. Spinal intramedullary teratoma with exophytic components. Neurosurg Rev. 2004;27:137–8.\nVercellini P, Vigano P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014;10:261–75.\nWang Y, Morrow JS. Identification and characterization of human SLP-2, a novel homologue of stomatin (band 7.2b) present in erythrocytes and other tissues. J Biol Chem. 2000;275:8062–71.\nZhang J, Song X, Li C, Tian Y. Expression and clinical significance of SLP-2 in ovarian tumors. Oncol Lett. 2019;17:4626–32.\nZhang X, Li BY, Fu LJ, Adu-Gyamfi EA, Xu BR, Liu TH, Chen XM, Lan X, Wang YX, Xu HB, et al. Stomatin-like protein 2 (SLP2) regulates the proliferation and invasion of trophoblast cells by modulating mitochondrial functions. Placenta. 2020;100:13–23.\nAcknowledgements\nThe authors thank the laboratory animal facilities at CSIR-CDRI, Lucknow, India and the patients for providing the samples at KGMU, Lucknow. The author also acknowledges Dr. J. V. Pratap for the critical reading of the manuscript and providing helpful comments. SK acknowledges fellowship from CSIR, New Delhi, India via file no. 31/04(1288)/2018-EMR-I. The CSIR-CDRI manuscript number is 10511.\nFunding\nThe study was supported by the DBT, New Delhi (Grant nos. BT/PR14480/MED/97/265/2015 and BT/PR30749/MED/97/421/2018) and CSIR, New Delhi (Grant no. MLP2026) sanctioned to RKJ.\nAuthor information\nAuthors and Affiliations\nContributions\nSK contributed in Figs. -1 A, B, and C, -2 (A–F), -3 (A, C, and D), and -4 RT contributed in Figs. -1 D and -3 B and E. PLS contributed in Fig.—1 A and B. AKK contributed in Fig. -1 A. In Fig.-3 D, SG contributed in the immunoblotting of SLP-2. RKJ coordinated the study, analyzed the data, and wrote the manuscript.\nCorresponding author\nEthics declarations\nEthics Approval\nThe study was under the approval of the institutional ethics committee for lab animal (IAEC/2018/97 dated 11–07-2019) and human subjects (192/Ethics/2020 dated 08–03-2019 and CDRI/IEC/2019/A7 dated 11 July 2019).\nConsent to Participate\nThe consent to participate was obtained from the patients.\nConsent for Publication\nThe authors consented for the publication.\nConflict of Interest\nThe authors declare no competing interests.\nAdditional information\nPublisher’s Note\nSpringer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.\nSupplementary Information\nBelow is the link to the electronic supplementary material.\nRights and permissions\nSpringer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.\nAbout this article\nCite this article\nKumari, S., Sankhwar, P., Tripathi, R. et al. Stomatin-like Protein-2 Promotes Aggregation, Colonization and Migration of Endometriotic Cells. Reprod. Sci. 30, 1854–1866 (2023). https://doi.org/10.1007/s43032-022-01139-y\nReceived:\nAccepted:\nPublished:\nVersion of record:\nIssue date:\nDOI: https://doi.org/10.1007/s43032-022-01139-y","source_license":"public-domain-us","license_restricted":false}