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Overexpression of Four Joint Box-I Protein (FJXI) in Eutopic Endometrium From Women With Endometriosis

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Abstract

The four jointed box I (FJXI) is a regulator of angiogenesis, and the levels of FJXI are increased in several types of cancer. Angiogenesis plays a critical role in endometrial growth as well as in several gynecologic disorders including endometriosis. However, the function of FJXI has not been studied in endometriosis. Therefore, we examined the levels of FJXI in eutopic endometrium from women with or without endometriosis. The levels of FJXI protein did not change in endometrial cells during the menstrual cycle in endometrium from women without endometriosis. However, its levels were significantly higher in the secretory phase of the eutopic endometrium from women with endometriosis when compared to women without endometriosis. Hypoxia-inducible factor-1 a (HIF 1 α) is known as a key mediator of endometriosis by regulating genes essential to estrogen production, angiogenesis, proliferation, inflammation, and extracellular invasion. It has been reported that FJXI induces an increase in HIF 1 α through posttranslational stabilization. The results of our Western blot analysis reveal a significant positive correlation between FJXI and HIF 1 α proteins in endometrium of women with and without endometriosis. This overexpression of FJXI was confirmed by sequential analysis of the eutopic endometrium during endometriosis progression, using an induced model of endometriosis in the baboon. Therefore, our results suggest that high levels of FJXI proteins may play an important role in the pathogenesis of endometriosis.

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References

  1. Burney RO, Giudice LC. Pathogenesis and pathophysiology of endometriosis. Fertil Steril. 2012;98(3):511–519.

    CAS  PubMed  Google Scholar 

  2. Leone Roberti Maggiore U, Ferrero S, Mangili G, et al. A systematic review on endometriosis during pregnancy: diagnosis, misdiagnosis, complications and outcomes. Hum Reprod Update. 2016;22(1):70–103.

    PubMed  Google Scholar 

  3. Sampson JA. Metastatic or embolic endometriosis, due to the menstrual dissemination of endometrial tissue into the venous circulation. Am J Pathol. 1927;3(2):93–110.143.

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Laschke MW, Menger MD. In vitro and in vivo approaches to study angiogenesis in the pathophysiology and therapy of endometriosis. Hum Reprod Update. 2007;13(4):331–342.

    CAS  PubMed  Google Scholar 

  5. McLaren J. Vascular endothelial growth factor and endometriotic angiogenesis. Hum Reprod Update. 2000;6(1):45–55.

    CAS  PubMed  Google Scholar 

  6. Di Carlo C, Bonifacio M, Tommaselli GA, Bifulco G, Guerra G, Nappi C. Metalloproteinases, vascular endothelial growth factor, and angiopoietin 1 and 2 in eutopic and ectopic endometrium. Fertil Steril. 2009;91(6):2315–2323.

    PubMed  Google Scholar 

  7. Popovici RM, Irwin JC, Giaccia AJ, Giudice LC. Hypoxia and cAMP stimulate vascular endothelial growth factor (VEGF) in human endometrial stromal cells: potential relevance to menstruation and endometrial regeneration. J Clin Endocrinol Metab. 1999;84(6):2245–2248.

    CAS  PubMed  Google Scholar 

  8. Rocha AL, Reis FM, Taylor RN. Angiogenesis and endometriosis. Obstet Gynecol Int. 2013;2013:859619.

    Google Scholar 

  9. Pugh CW, Ratcliffe PJ. Regulation of angiogenesis by hypoxia: role of the HIF system. Nat Med. 2003;9(6):677–684.

    CAS  PubMed  Google Scholar 

  10. Critchley HO, Osei J, Henderson TA, et al. Hypoxia-inducible factor-lalpha expression in human endometrium and its regulation by prostaglandin E-series prostanoid receptor 2 (EP2). Endocrinology. 2006;147(2):744–753.

    CAS  PubMed  Google Scholar 

  11. Wu MH, Chen KF, Lin SC, Lgu CW, Tsai SJ. Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-lalpha. Am J Pathol. 2007;170(2):590–598.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Goteri G, Lucarini G, Montik N, et al. Expression of vascular endothelial growth factor (VEGF), hypoxia inducible factor-lalpha (HIF-lalpha), and microvessel density in endometrial tissue in women with adenomyosis. Int J Gynecol Pathol. 2009;28(2):157–163.

    PubMed  Google Scholar 

  13. Kim BG, Yoo JY, Kim TH, et al. Aberrant activation of signal transducer and activator of transcription-3 (STAT3) signaling in endometriosis. Hum Reprod. 2015;30(5):1069–1078.

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Zhang ZZ, Hu CP, Tang WW, et al. Wenshen Xiaozheng Tang suppresses the growth of endometriosis with an antiangiogenic effect. Climacteric. 2013;16(6):700–708.

    CAS  PubMed  Google Scholar 

  15. Tsai CH, Li CH, Liao PL, et al. NcoA2-dependent inhibition of HIF-lalpha activation is regulated via AhR. Toxicol Sci. 2015;148(2):517–530.

    CAS  PubMed  Google Scholar 

  16. Abu-Remaileh M, Aqeilan RI. Tumor suppressor WWOX regulates glucose metabolism via HIFlalpha modulation. Cell Death Differ. 2014;21(11):1805–1814.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Jiang Y, Wu GH, He GD, et al. The effect of silencing HIF-lalpha gene in BxPC-3 cell line on glycolysis-related gene expression, cell growth, invasion, and apoptosis. Nutr Cancer. 2015;67(8):1314–1323.

    PubMed  Google Scholar 

  18. Timani KA, Liu Y, Fan Y, Mohammad KS, He JJ. Tip110 regulates the cross talk between p53 and hypoxia-inducible factor 1alpha under hypoxia and promotes survival of cancer cells. Mol Cell Biol. 2015;35(13):2254–2264.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Semenza GL. Oxygen sensing, homeostasis, and disease. NEnglJ Med. 2011;365(6):537–547.

    CAS  Google Scholar 

  20. Afshar Y, Miele L, Fazleabas AT. Notchl is regulated by chorionic gonadotropin and progesterone in endometrial stromal cells and modulates decidualization in primates. Endocrinology. 2012;153(6):2884–2896.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Jarvinen AK, Autio R, Kilpinen S, et al. High-resolution copy number and gene expression microarray analyses of head and neck squamous cell carcinoma cell lines of tongue and larynx. Genes Chromosomes Cancer. 2008;47(6):500–509.

    CAS  PubMed  Google Scholar 

  22. Al-Greene NT, Means AL, Lu P, et al. Four jointed box 1 promotes angiogenesis and is associated with poor patient survival in colorectal carcinoma. PLoS One. 2013;8(7):e69660.

    CAS  PubMed  PubMed Central  Google Scholar 

  23. Chai SJ, Yap YY, Foo YC, et al. Identification of four-jointed box 1 (FJXl)-specific peptides for immunotherapy of nasopharyngeal carcinoma. PLoS One. 2015;10(11):e0130464.

    PubMed  PubMed Central  Google Scholar 

  24. Wang HW, Huang TS, Lo HH, et al. Deficiency of the micro-RNA-31-microRNA-720 pathway in the plasma and endothelial progenitor cells from patients with coronary artery disease. Arter-ioscler Thromb Vase Biol. 2014;34(4):857–869.

    CAS  Google Scholar 

  25. Afshar Y, Hastings J, Roqueiro D, Jeong JW, Giudice LC, Fazleabas AT. Changes in eutopic endometrial gene expression during the progression of experimental endometriosis in the baboon, Papio anubis. Biol Reprod. 2013;88(2):44.

    PubMed  PubMed Central  Google Scholar 

  26. Ishibashi H, Suzuki T, Suzuki S, et al. Sex steroid hormone receptors in human thymoma. J Clin Endocrinol Metab. 2003;88(5):2309–2317.

    CAS  PubMed  Google Scholar 

  27. Zhan L, Wang W, Zhang Y, Song E, Fan Y, Wei B. Hypoxia-inducible factor-1alpha: a promising therapeutic target in endometriosis. Biochimie. 2016;123:130–137.

    CAS  PubMed  Google Scholar 

  28. Fazleabas AT, Brudney A, Gurates B, Chai D, Bulun S. A modified baboon model for endometriosis. Ann N Y Acad Sci. 2002;955:308–317. discussion 340-302, 396-406.

    PubMed  Google Scholar 

  29. Braundmeier AG, Fazleabas AT. The non-human primate model of endometriosis: research and implications for fecundity. Mol Hum Reprod. 2009;15(10):577–586.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. D’Hooghe TM, Kyama CM, Chai D, et al. Nonhuman primate models for translational research in endometriosis. Reprod Sci. 2009;16(2):152–161.

    PubMed  Google Scholar 

  31. Ashery-Padan R, Alvarez-Bolado G, Klamt B, Gessler M, Gruss P. Fjxl, the murine homologue of the Drosophila four-jointed gene, codes for a putative secreted protein expressed in restricted domains of the developing and adult brain. Mech Dev. 1999;80(2):213–217.

    CAS  PubMed  Google Scholar 

  32. Rock R, Heinrich AC, Schumacher N, Gessler M. Fjxl: a notch-inducible secreted ligand with specific binding sites in developing mouse embryos and adult brain. Dev Dyn. 2005;234(3):602–612.

    CAS  PubMed  Google Scholar 

  33. Tokunaga C, Gerhart JC. The effect of growth and joint formation on bristle pattern in D melanogaster. J Exp Zool. 1976;198(1):79–95.

    CAS  PubMed  Google Scholar 

  34. Yang CH, Axelrod JD, Simon MA. Regulation of frizzled by fatlike cadherins during planar polarity signaling in the Drosophila compound eye. Cell. 2002;108(5):675–688.

    CAS  PubMed  Google Scholar 

  35. Ishikawa HO, Takeuchi H, Haltiwanger RS, Irvine KD. Four-jointed is a Golgi kinase that phosphorylates a subset of cadherin domains. Science. 2008;321(5887):401–404.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Bao Y, Hata Y, Ikeda M, Withanage K. Mammalian Hippo pathway: from development to cancer and beyond. J Biochem. 2011;149(4):361–379.

    CAS  PubMed  Google Scholar 

  37. Buckles GR, Rauskolb C, Villano JL, Katz FN. Four-jointed interacts with dachs, abelson and enabled and feeds back onto the Notch pathway to affect growth and segmentation in the Drosophila leg. Development. 2001;128(18):3533–3542.

    CAS  PubMed  Google Scholar 

  38. Gutierrez-Avino FJ, Ferres-Marco D, Dominguez M. The position and function of the Notch-mediated eye growth organizer: the roles of JAK/STAT and four-jointed. EMBO Rep. 2009;10(9):1051–1058.

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Buckanovich RJ, Sasaroli D, O’Brien-Jenkins A, et al. Tumor vascular proteins as biomarkers in ovarian cancer. J Clin Oncol. 2007;25(7):852–861.

    CAS  PubMed  Google Scholar 

  40. Zeidler MP, Perrimon N, Strutt DI. The four-jointed gene is required in the Drosophila eye for ommatidial polarity specification. Curr Biol. 1999;9(23):1363–1372.

    CAS  PubMed  Google Scholar 

  41. He H, Liu R, Xiong W, et al. Lentiviral vector-mediated down-regulation of Notchl in endometrial stem cells results in proliferation and migration in endometriosis. Mol Cell Endocrinol. 2016;434:210–218.

    CAS  PubMed  Google Scholar 

  42. Hsiao KY, Chang N, Lin SC, Li YH, Wu MH. Inhibition of dual specificity phosphatase-2 by hypoxia promotes interleukin-8-mediated angiogenesis in endometriosis. Hum Reprod. 2014;29(12):2747–2755.

    CAS  PubMed  Google Scholar 

  43. Wu MH, Lin SC, Hsiao KY, Tsai SJ. Hypoxia-inhibited dual-specificity phosphatase-2 expression in endometriotic cells regulates cyclooxygenase-2 expression. J Pathol. 2011;225(3):390–400.

    CAS  PubMed  Google Scholar 

  44. Johnson JC, Schmidt CR, Shrubsole MJ, et al. Urine PGE-M: a metabolite of prostaglandin E2 as a potential biomarker of advanced colorectal neoplasia. Clin Gastroenterol Hepatol. 2006;4(11):1358–1365.

    CAS  PubMed  Google Scholar 

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Correspondence to Jae-Wook Jeong PhD.

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Chang, H.J., Yoo, JY., Kim, T.H. et al. Overexpression of Four Joint Box-I Protein (FJXI) in Eutopic Endometrium From Women With Endometriosis. Reprod. Sci. 25, 207–213 (2018). https://doi.org/10.1177/1933719117716780

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