Depleted lamin B1: a possible marker of the involvement of senescence in endometriosis?

Propose Endometriosis is a benign disease characterized by implantation and the growth of endometrial tissue outside the uterine cavity and it shares similarities with cancer. Lamin B1, p16 and p21 play a role on cell cycle regulation, development, cell repair and its activities are related to cancers. Considering the similarities between endometriosis and cancer, the aim of the present cross-sectional study is to detect p16, p21 and Lamin B1 in the ectopic endometrium of patients with endometriosis (n = 8) with eutopic (n = 8) and control endometrium (n = 8) and relate them to the maintenance and development of endometriosis.

Biopsies were obtained from both eutopic and ectopic, from deep infiltrating lesions, endometrium frozen and used for immunofluorescent (p16) or immunohistochemistry procedures (p16, p21, lamin B1).

Detected higher lamin B1 in the eutopic endometrium when compared with ectopic endometrium, with no differences between endometriosis tissue with control endometrium. Similar presence of p16 in all groups of patients and no p21 detection was observed.

We observed reduced detection of lamin B1 in the ectopic endometrium raising the possibility that the presence of senescent cells might be contributing to the maintenance and progression of endometriosis by apoptosis resistance and peritoneal stress inherent of the disease. Similar content being viewed by others

Fuldeore M, Yang H, Du EX, Soliman AM, Wu EQ, Winkel C (2015) Healthcare utilization and costs in women diagnosed with endometriosis before and after diagnosis: a longitudinal analysis of claims databases. Fertil Steril 103(1):163–171. https://doi.org/10.1016/j.fertnstert.2014.10.011 Bulletti C, Coccia ME, Battistoni S, Borini A (2010) Endometriosis and infertility. J Assist Reprod Genet 27:441–447 De Graaff AA, Dirksen CD, Simoens S, De Bie B, Hummelshoj L, D’Hooghe TM et al (2015) Quality of life outcomes in women with endometriosis are highly influenced by recruitment strategies. Hum Reprod 30(6):1331–1341 De Graaff AA, D’hooghe TM, Dunselman GAJ, Dirksen CD, Hummelshoj L, Simoens S et al (2013) The significant effect of endometriosis on physical, mental and social wellbeing: results from an international cross-sectional survey. Hum Reprod 28(10):2677–2685 Vercellini P, Viganò P, Somigliana E, Fedele L (2014) Endometriosis: pathogenesis and treatment. Nat Rev 10(5):261–275. http://www.nature.com/doifinder/10.1038/nrendo.2013.255%5Cn, http://www.ncbi.nlm.nih.gov/pubmed/24366116 Signorile PG, Baldi A (2010) Endometriosis: new concepts in the pathogenesis. Int J Biochem Cell Biol 42(6):778–780. http://www.sciencedirect.com/science/article/pii/S1357272510001196 Nnoaham KE, Hummelshoj L, Webster P, D’Hooghe T, De Cicco Nardone F, De Cicco Nardone C et al (2011) Impact of endometriosis on quality of life and work productivity: a multicenter study across ten countries. Fertil Steril 96(2):366–373. https://doi.org/10.1016/j.fertnstert.2011.05.090 Culley L, Law C, Hudson N, Denny E, Mitchell H, Baumgarten M et al (2013) The social and psychological impact of endometriosis on women’s lives: a critical narrative review. Hum Reprod Update. 19(6):625–639 Zubrzycka A, Zubrzycki M, Janecka A, Zubrzycka M (2015) New horizons in the etiopathogenesis and non-invasive diagnosis of endometriosis. Curr Mol Med 15(8):697–713 Agarwal A, Gupta S, Sharma RK (2005) Role of oxidative stress in female reproduction. Reprod Biol Endocrinol 3:28 Bellelis P, Podgaec S, Abrão MS (2014) Fatores ambientais e endometriose: um ponto de vista. Rev Bras Ginecol e Obs 36(10):433–435. http://www.scielo.br/scielo.php?script=sci_arttext&pid=S0100-72032014001000433&lng=en&nrm=iso&tlng=en Kyama CM, Debrock S, Mwenda JM, D’Hooghe TM (2003) Potential involvement of the immune system in the development of endometriosis. Reprod Biol Endocrinol 1:123. http://www.ncbi.nlm.nih.gov/pubmed/14651748%5Cn, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC305339 Somigliana E, Vigano P, Parazzini F, Stoppelli S, Giambattista E, Vercellini P (2006) Association between endometriosis and cancer: a comprehensive review and a critical analysis of clinical and epidemiological evidence. Gynecol Oncol 101(2):331–341 Bassi MA, Arias V, Filho ND, Gueuvoghlanian-Silva BY, Abrao MS, Podgaec S (2015) Deep invasive endometriosis lesions of the rectosigmoid may be related to alterations in cell kinetics. Reprod Sci 22(9):1122–1128. http://journals.sagepub.com/doi/10.1177/1933719115574341 Pupo-Nogueira A, de Oliveira RM, Petta CA, Podgaec S, Dias JA, Abrao MS (2007) Vascular endothelial growth factor concentrations in the serum and peritoneal fluid of women with endometriosis. Int J Gynaecol Obstet 99(1):33–37. http://www.ncbi.nlm.nih.gov/pubmed/17602688 Bessa NZ, de Francisco Oliveira D, Paula Andres M, Gueuvoghlanian-Silva BY, Podgaec S, Fridman C (2016) Polymorphisms of ICAM-1 and IL-6 genes related to endometriosis in a sample of Brazilian women. J Assist Reprod Genet 33(11):1487–1492. https://doi.org/10.1007/s10815-016-0796-z Varma R, Rollason T, Gupta JK, Maher ER (2004) Endometriosis and the neoplastic process. Reproduction 127(3):293–304 Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70. http://www.ncbi.nlm.nih.gov/pubmed/10647931 Pavone ME, Lyttle BM (2015) Endometriosis and ovarian cancer: links, risks, and challenges faced. Int J Womens Health 7:663–672 Anglesio MS, Papadopoulos N, Ayhan A, Nazeran TM, Noë M, Horlings HM et al (2017) Cancer-associated mutations in endometriosis without cancer. N Engl J Med 376(19):1835–1848. https://doi.org/10.1056/NEJMoa1614814 Chao C, Herr D, Chun J, Xu Y (2006) Ser18 and 23 phosphorylation is required for p53-dependent apoptosis and tumor suppression. EMBO J 25(11):2615–2622. http://www.ncbi.nlm.nih.gov/pubmed/16757976%5Cn, http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=PMC1478190 Hirakawa T, Nasu K, Abe W, Aoyagi Y, Okamoto M, Kai K et al (2016) MiR-503, a microRNA epigenetically repressed in endometriosis, induces apoptosis and cell-cycle arrest and inhibits cell proliferation, angiogenesis, and contractility of human ovarian endometriotic stromal cells. Hum Reprod 31(11):2587–2597 Munoz-Espin D, Serrano M (2014) Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol 15(7):482–496. https://doi.org/10.1038/nrm3823 Dutto I, Tillhon M, Cazzalini O, Stivala LA, Prosperi E (2014) Biology of the cell cycle inhibitor p21CDKN1A: molecular mechanisms and relevance in chemical toxicology. Arch Toxicol 89:155–178 Ressler S, Bartkova J, Niederegger H, Bartek J, Scharffetter-Kochanek K, Jansen-Dürr P et al (2006) p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging Cell 5(5):379–389 Li J, Poi MJ, Tsai M-D (2011) The regulatory mechanisms of tumor supressor p16INK4 and relevance to cancer. J Biochem 50(25):5566–5582 Davalos AR, Coppe JP, Campisi J, Desprez PY (2010) Senescent cells as a source of inflammatory factors for tumor progression. Cancer Metastasis Rev 29:273–283 Yoon N, Yoon G, Park CK, Kim H-S (2016) Stromal p16 expression is significantly increased in malignant ovarian neoplasms. Oncotarget 7(40). www.impactjournals.com/oncotarget Svensson S, Nilsson K, Ringberg A, Landberg G (2003) Invade or proliferate? Two contrasting events in malignant behavior governed by p16INK4a and an intact Rb pathway illustrated by a model system of basal cell carcinoma. Cancer Res 63(8):1737–1742 Fauvet R, Poncelet C, Hugol D, Lavaur A, Feldmann G, Daraï E (2003) Expression of apoptosis-related proteins in endometriomas and benign and malignant ovarian tumours. Virchows Arch 443(1):38–43 Stewart CJR, Bharat C (2016) Clinicopathological and immunohistological features of polypoid endometriosis. Histopathology 68(3):398–404 Ohtani N, Hara E (2013) Roles and mechanisms of cellular senescence in regulation of tissue homeostasis. Cancer Sci 104(5):525–530 Dou Z, Xu C, Donahue G, Shimi T, Pan J-A, Zhu J et al (2015) Autophagy mediates degradation of nuclear lamina. Nature 527(7576):1–17. http://www.nature.com/doifinder/10.1038/nature15548 Broers JLV, Ramaekers FCS (2014) The role of the nuclear lamina in cancer and apoptosis. Cancer Biol Nucl Envel 773:27–48. http://link.springer.com/10.1007/978-1-4899-8032-8 Li L, Du Y, Kong X, Li Z, Jia Z, Cui J et al (2013) Lamin B1 is a novel therapeutic target of betulinic acid in pancreatic cancer. Clin Cancer Res 19(17):4651–4661 Coradeghini R, Barboro P, Rubagotti A, Boccardo F, Parodi S, Carmignani G et al (2006) Differential expression of nuclear lamins in normal\nand cancerous prostate tissues. Oncol Rep 15(3):609–613. http://www.spandidos-publications.com/or/15/3/609/abstract Sun S, Xu MZ, Poon RT, Day PJ, Luk JM (2010) Circulating lamin B1 (LMNB1) biomarker detects early stages of liver cancer in patients. J Proteome Res 9(1):70–78 Moss SF, Krivosheyev V, de Souza A, Chin K, Gaetz HP, Chaudhary N et al (1999) Decreased and aberrant nuclear lamin expression in gastrointestinal tract neoplasms. Gut 45(5):723–729. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=10517909 Abrao MS, Podgaec S, Dias JA, Averbach M, Garry R, Ferraz Silva LF et al (2006) Deeply infiltrating endometriosis affecting the rectum and lymph nodes. Fertil Steril 86(3):543–547 Park YS, Kim S, Oh SH, Park HJ, Lee S, Il Kim T et al (2014) Comparison of alveolar ridge preservation methods using three-dimensional micro-computed tomographic analysis and two-dimensional histometric evaluation. Imaging Sci Dent. 44(2):143–148 El-Domyati M, Hosam W, Abdel Azim E, Abdel-Wahab H, Mohamed E (2016) Microdermabrasion: a clinical, histometric, and histopathologic study. J Cosmet Dermatol 15:503–513 Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Erlbaum, New York Dreesen O, Ong PF, Chojnowski A, Colman A (2013) The contrasting roles of lamin B1 in cellular aging and human disease. Nucleus 4(4):283–290. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3810336&tool=pmcentrez&rendertype=abstract Camps J, Erdos MR, Ried T (2015) The role of lamin B1 for the maintenance of nuclear structure and function. Nucleus 6(1):8–14. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4615282/ Wazir U, Ahmed MH, Bridger JM, Harvey A, Jiang WG, Sharma AK et al (2013) The clinicopathological significance of lamin A/C, lamin B1 and lamin B receptor mRNA expression in human breast cancer. Cell Mol Biol Lett 18(4):595–611. http://www.degruyter.com/view/j/cmble.2013.18.issue-4/s11658-013-0109-9/s11658-013-0109-9.xml Camps J, Wangsa D, Falke M, Brown M, Case CM, Erdos MR et al (2014) Loss of lamin B1 results in prolongation of S phase and decondensation of chromosome territories. FASEB J. 28(8):3423–3434 Freund A, Laberge R-M, Demaria M, Campisi J (2012) Lamin B1 loss is a senescence-associated biomarker. Mol Biol Cell 23(11):2066–2075. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3364172&tool=pmcentrez&rendertype=abstract Freund A, Orjalo AV, Desprez PY, Campisi J (2010) Inflammatory networks during cellular senescence: causes and consequences. Trends Mol Med 16(5):238–246. https://doi.org/10.1016/j.molmed.2010.03.003 Scaffidi P, Misteli T (2005) Reversal of the cellular phenotype in the premature aging disease Hutchinson-Gilford progeria syndrome. Nat Med 11(4):440–445. http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1351119&tool=pmcentrez&rendertype=abstract Dreesen O, Chojnowski A, Ong PF, Zhao TY, Common JE, Lunny D et al (2013) Lamin B1 fluctuations have differential effects on cellular proliferation and senescence. J Cell Biol 200(5):605–617 Shimi T, Butin-israeli V, Adam SA, Hamanaka RB, Goldman AE, Lucas CA et al (2011) The role of nuclear lamin B1 in cell proliferation and senescence the role of nuclear lamin B1 in cell proliferation and senescence. Genes Dev 25:2579–2593 Shah PP, Donahue G, Otte GL, Capell BC, Nelson DM, Cao K et al (2013) Lamin B1 depletion in senescent cells triggers large-scale changes in gene expression and the chromatin landscape. Genes Dev 27(16):1787–1799 Dutta EH, Behnia F, Boldogh I, Saade GR, Taylor BD, Kacerovský M et al (2015) Oxidative stress damage-associated molecular signaling pathways differentiate spontaneous preterm birth and preterm premature rupture of the membranes. Mol Hum Reprod 22(2):143–157 Pirdel L, Pirdel M (2014) Role of iron overload-induced macrophage apoptosis in the pathogenesis of peritoneal endometriosis. Reproduction 147:199 Mier-Cabrera J, Jiménez-Zamudio L, García-Latorre E, Cruz-Orozco O, Hernández-Guerrero C (2011) Quantitative and qualitative peritoneal immune profiles, T-cell apoptosis and oxidative stress-associated characteristics in women with minimal and mild endometriosis. BJOG An Int J Obstet Gynaecol 118(1):6–16 Harlev A, Gupta S, Agarwal A (2015) Targeting oxidative stress to treat endometriosis. Expert Opin Ther Targets 19:1447–1464. https://doi.org/10.1517/14728222.2015.1077226 Augoulea A, Alexandrou A, Creatsa M et al (2012) Pathogenesis of endometriosis: the role of genetics, inflammation and oxidative stress. Arch Gynecol Obstet 286:99–103. https://doi.org/10.1007/s00404-012-2357-8 Huhtinen K, Ståhle M, Perheentupa A, Poutanen M (2012) Estrogen biosynthesis and signaling in endometriosis. Mol Cell Endocrinol 358:146–154. https://doi.org/10.1016/j.mce.2011.08.022 Piccinato CA, Neme RM, Torres N et al (2016) Increased expression of CYP1A1 and CYP1B1 in ovarian/peritoneal endometriotic lesions. Reproduction 151:683–692. https://doi.org/10.1530/REP-15-0581 Foster JS, Henley DC, Bukovsky A et al (2001) Multifaceted regulation of cell cycle progression by estrogen: regulation of Cdk inhibitors and Cdc25A independent of cyclin D1-Cdk4 function. Mol Cell Biol 21:794–810. https://doi.org/10.1128/MCB.21.3.794-810.2001 Moritani S, Ichihara S, Hasegawa M et al (2012) Stromal p16 expression differentiates endometrial polyp from endometrial hyperplasia. Virchows Arch 461:141–148. https://doi.org/10.1007/s00428-012-1276-1

We would like to thank Aline da Silva and Helen Mendes for technical assistance during sample collection and processing. Author information Authors and Affiliations Contributions H Malvezzi: Protocol/project development; Data collection or management; Data analysis; Manuscript writing/editing, BG Viana: Data collection or management, C Dobo: Data collection or management, RZ Filippi: Data collection or management, S Podgaec: Protocol/project development, Data collection or management; Data analysis; Manuscript writing/editing, CA Piccinato: Protocol/project development; Data collection or management; Data analysis; Manuscript writing/editing. Corresponding author Ethics declarations Conflicts of interest Helena Malvezzi declares that she has no conflict of interest. Bruno Gallani Viana declares that he has no conflict of interest. Cristine Dobo declares that she has no conflict of interest. Renee Zon Filippi declares that she has no conflict of interest. Sérgio Podgaec declares that he has no conflict of interest. Carla Azevedo Piccinato declares that she has no conflict of interest. Ethical approval This article does not contain any studies with animals performed by any of the authors. Human and animal rights All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The study was approved by the Committee on Human Research of the Hospital Albert Einstein (Number 56229916.9.0000.0071; São Paulo, Brazil), which is part of the Ethics Committee of the Brazilian Ministry of Health (CONEP) on July 13th, 2016. Informed consent Informed consent was obtained from all individual participants included in the study. All patients provided informed consent after the nature of the study was fully explained, and institutional review board approval. Electronic supplementary material Below is the link to the electronic supplementary material. Rights and permissions About this article Cite this article Malvezzi, H., Viana, B.G., Dobo, C. et al. Depleted lamin B1: a possible marker of the involvement of senescence in endometriosis?. Arch Gynecol Obstet 297, 977–984 (2018). https://doi.org/10.1007/s00404-018-4691-y Received: Accepted: Published: Version of record: Issue date: DOI: https://doi.org/10.1007/s00404-018-4691-y