Abstract
The present study investigated expression and protein localization of FOXL2 messenger RNA (mRNA) in endometrium of healthy women and in patients with endometriosis during endometrial cycle. In endometriotic lesions, FOXL2 mRNA and protein were evaluated and a possible correlation with activin A mRNA expression changes was also studied. Endometrium was collected from healthy women (n = 52) and from women with endometriosis (n = 31) by hysteroscopy; endometriotic tissues were collected by laparoscopy (n = 38). FOXL2 gene expression analysis in endometrium of healthy women showed a significant expression and no significant changes in mRNA levels between proliferative and secretory phases; a similar pattern was observed in endometrium of patients with endometriosis. Immunohistochemical evaluation showed that FOXL2 protein localized in stromal and glandular cells and colocalized with SUMO-1. FOXL2 mRNA expression was 3-fold higher in endometriosis than in healthy endometrium (P < .01) and a positive correlation between FOXL2 and activin A mRNA was found (P < .05) in endometriosis. In conclusion, FOXL2 mRNA expression and its protein localization do not change during endometrial cycle in eutopic endometrium from healthy individuals or patients with endometriosis; the hyperexpression of FOXL2 in endometriotic lesions suggests an involvement of this transcriptional regulator, probably associated with activin A expression and related to the pathogenesis of endometriosis.
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Hannenhalli S, Kaestner KH. The evolution of Fox genes and their role in development and disease. Nat Rev Genet. 2009;10(4):233–240.
Grinius L, Kessler C, Schroeder J, Handwerger S. Forkhead transcription factor FOXO1A is critical for induction of human decidualization. J Endocrinol. 2006;189(1):179–187.
Takano M, Lu Z, Goto T, et al. Transcriptional cross talk between the forkhead transcription factor forkhead box O1A and the progesterone receptor coordinates cell cycle regulation and differentiation in human endometrial stromal cells. Mol Endocrinol. 2007;21(10):2334–2349.
Fu L, Girling JE, Rogers PA. Expression of Fox head protein 1 in human eutopic endometrium and endometriosis. Reprod Sci. 2008;15(3):243–252.
Christian M, Lam EW, Wilson MS, Brosens JJ. FOXO transcription factors and their role in disorders of the female reproductive tract. Curr Drug Targets. 2011;12(9):1291–1302.
Geiss-Friedlander R, Melchior F. Concepts in SUMO-lylation: a decade on. Nat Rev Mol Cell Biol. 2007;8(12):947–956.
Ellsworth BS, Burns AT, Escudero KW, Duval DL, Nelson SE, Clay CM. The gonadotropin releasing hormone (GnRH) receptor activating sequence (GRAS) is a composite regulatory element that interacts with multiple classes of transcription factors including Smads, AP-1 and a forkhead DNA binding protein. Mol Cell Endocrinol. 2003;206(1–2):93–111.
Blount AL, Schmidt K, Justice NJ, Vale WW, Fischer WH, Bilezikjian LM. FoxL2 and Smad3 coordinately regulate follistatin gene transcription. J Biol Chem. 2009;284(12):7631–7645.
Coss D, Mellon PL, Thackray VG. A FoxL in the Smad house: activin regulation of FSH. Trends Endocrinol Metab. 2010;21(9):562–568.
Schmidt D, Ovitt CE, Anlag K, et al. The murine winged-helix transcription factor Foxl2 is required for granulosa cell differentiation and ovary maintenance. Development. 2004;131(4):933–942.
Ottolenghi C, Omari S, Garcia-Ortiz JE, et al. Fox12 is required for commitment to ovary differentiation. Hum Mol Genet. 2005;14(14):2053–2062.
Pisarska MD, Bae J, Klein C, Hsueh AJ. Forkhead 12 is expressed in the ovary and represses the promoter activity of the steroidogenic acute regulatory gene. Endocrinol. 2004;145(7):3424–3433.
Nelson LM, Covington SN, Rebar RW. An update: spontaneous premature ovarian failure is not an early menopause. Fertil Steril. 2005;83(5):1327–1332.
Jones MC, Fusi L, Higham JH, et al. Regulation of the SUMO-1 pathway sensitizes differentiating human endometrial stromal cells to progesterone. Proc Natl Acad Sci U S A. 2006;103(44):16272–16277.
Al-Sabbagh M, Lam EW, Brosens JJ. Mechanisms of endometrial progesterone resistance. Mol Cell Endocrinol. 2012;358(2):208–215.
Kuo FT, Bentsi-Barnes IK, Barlow GM, Bae J, Pisarska MD. Sumoylation of forkhead L2 by Ubc9 is required for its activity as a transcriptional repressor of the steroidogenic acute regulatory gene. Cell Signal. 2009;21(12):1935–1944.
Florio P, Severi FM, Luisi S, et al. Endometrial expression and secretion of activin A, but not follistatin, increase in the secretory phase of the menstrual cycle. J Soc Gynecol Invest. 2003; 10(4):237–243.
Jones RL, Salamonsen LA, Findlay JK. Activin A promotes human endometrial stromal cell decidualization in vitro. J Clin Endocrinol Metab. 2002;87(8):4001–4004.
Jones RL, Findlay JK, Farnworth PG, Robertson DM, Wallace E, Salamonsen LA. Activin A and inhibin A differentially regulate human uterine matrix metalloproteinases: potential interactions during decidualization and Trophoblast invasion. Endocrinol. 2006;147(2):724–732.
Florio P, Gabbanini M, Borges LE, et al. Activins and related proteins in the establishment of pregnancy. Reprod Sci. 2010;17(4):320–330.
Reis FM, Di Blasio AM, Florio P, Ambrosini G, Di Loreto C, Petraglia F. Evidence for local production of inhibin A and activin A in patients with ovarian endometriosis. Fertil Steril. 2001;75(2):367–373.
Rocha AL, Carrarelli P, Novembri R, et al. Altered expression of activin, cripto, and follistatin in the endometrium of women with endometrioma. Fertil Steril. 2011;95(7):2241–2246.
Mangioni S, Viganò P, Florio P, et al. Effect of activin A on tumor necrosis factor-alpha/intercellular adhesion molecule-1 pathway in endometrial stromal cells. Eur J Obstet Gynecol Reprod Biol. 2005;123(2):218–223.
Rocha AL, Carrarelli P, Novembri R, et al. Activin A stimulates interleukin 8 and vascular endothelial growth factor release from cultured human endometrial stromal cells: possible implications for the pathogenesis of endometriosis. Reprod Sci. 2012;19(8):832–838.
Ferreira MC, Witz CA, Hammes LS, et al. Activin A increases invasiveness of endometrial cells in a in vitro model of human peritoneum. Mol Hum Reprod. 2008;14(5):301–307.
Eozenou C, Vitorino Carvalho A, Forde N, Giraud-Delville C, Gall L, Lonergan P. FOXL2 is regulated during the bovine estrous cycle and its expression in the endometrium is independent of conceptus-derived interferon Tau. Biol Reprod. 2012;87(2):1–9.
Honda H, Barrueto FF, Gogusev J, Im DD, Morin PJ. Serial analysis of gene expression reveals differential expression between endometriosis and normal endometrium. Possible roles for AXL and SHC1 in the pathogenesis of endometriosis. Reprod Biol Endocrinol. 2008;6:59.
Borghese B, Mondon F, Noël JC, et al. Gene expression profile for ectopic versus eutopic endometrium provides new insights into endometriosis oncogenic potential. Mol Endocrinol. 2008;22(11):2557–2562.
Chung TK, Cheung TH, Huen NY, et al. Dysregulated micro-RNAs and their predicted targets associated with endometrioid endometrial adenocarcinoma in Hong Kong women. Int J Cancer. 2009;124(6):1358–1365.
The American fertility society revised American fertility society classification of endometriosis. Fertil Steril. 1985;43(3):351–352.
Noyes RW, Hertig AT, Rock J. Dating the endometrial biopsy. Am J Obstet Gynecol. 1975;122(2):262–263.
Marongiu M, Deiana M, Meloni A, et al. The forkhead transcription factor Foxl2 is SUMO-lylated in both human and mouse: SUMO-lylation affects its stability, localization, and activity. PLoS One. 2010;5(3):e9477.
Kim JJ, Buzzio OL, Li S, Lu Z. Role of FOXO1A in the regulation of insulin-like growth factor-binding protein-1 in human endometrial cells: interaction with progesterone receptor. Biol Reprod. 2005;73(4):833–839.
Uhlenhaut NH, Jakob S, Anlag K, et al. Somatic sex reprogramming of adult ovaries to testes by FOXL2 ablation. Cell. 2009;139(6):1130–1142.
Shah SP, Köbel M, Senz J, et al. Mutation of FOXL2 in granulosacell tumors of the ovary. N Engl J Med. 2009;360(26):2719–2729.
Weigel D, Jürgens G, Küttner F, Seifert E, Jäckle H. The homeotic gene fork head encodes a nuclear protein and is expressed in the terminal regions of the Drosophila embryo. Cell. 1989;57(4):645–658.
Ghochani Y, Saini JK, Mellon PL, Thackray VG. FOXL2 is involved in the synergy between activin and progestins on the follicle-stimulating hormone β-subunit promoter. Endocrinol. 2012;153(4):2023–2033.
Shazand K, Baban S, Prive C, et al. FOXO1 and c-jun transcription factors mRNA are modulated in endometriosis. Mol Hum Reprod. 2004;10(12):871–877.
Batista F, Vaiman D, Dausset J, Fellous M, Veitia R. Potential targets of FOXL2, a transcription factor involved in craniofacial and follicular development, identified by transcriptomics. PNAS. 2007;104(9):3330–3335.
Bukulmez O, Hardy DB, Carr BR, Word RN, Mendelson CR. Inflammatory status influences aromatase and steroid receptor expression in endometriosis. Endocrinol. 2008;149(3):1190–1204.
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Governini, L., Carrarelli, P., Rocha, A.L.L. et al. FOXL2 in Human Endometrium: Hyperexpressed in Endometriosis. Reprod. Sci. 21, 1249–1255 (2014). https://doi.org/10.1177/1933719114522549
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DOI: https://doi.org/10.1177/1933719114522549