An investigation of the effects of endometriosis on the proteome of human eutopic endometrium: A heterogeneous tissue with a complex disease

The pathogenesis of endometriosis includes the proliferation of heterogeneous endometrial cells and their invasion into ectopic sites within the peritoneal cavity. This may be due to abnormalities of the eutopic endometrium itself, predisposing the cells to survive and implant ectopically. We investigated the applicability of 2‐DE gels and peptide mass mapping to identify candidate endometrial proteins with a role in endometriosis. Despite the heterogeneous nature of endometrium, our results show that combining the analysis of 2‐DE gels and peptide mass mapping yields consistent data. We identified dysregulated proteins in women with endometriosis which included: (i) molecular chaperones including heat shock protein 90 and annexin A2, (ii) proteins involved in cellular redox state, such as peroxiredoxin 2, (iii) proteins involved in protein and DNA formation/breakdown, including ribonucleoside‐diphosphate reductase, prohibitin and prolyl 4‐hydroxylase, and (iv) secreted proteins, such as apolipoprotein A1. These proteins have functions which suggest that they could play a role in the pathogenesis of endometriosis. This study demonstrated that 2‐DE gel analysis and mass spectroscopic protein identification are suitable for the identification of proteins with candidate associations with endometriosis. These techniques should be used on a larger scale to identify endometriosis‐related proteins, thus improving the understanding of this complex disease.

[1]  P. Fowler,et al.  Developmental Indices of Nutritionally Induced Placental Growth Restriction in the Adolescent Sheep , 2005, Pediatric Research.

[2]  E. Baumgart-Vogt,et al.  Peroxiredoxins, oxidative stress, and cell proliferation. , 2005, Antioxidants & redox signaling.

[3]  P. Koninckx,et al.  CA-125 and placental protein 14 concentrations in plasma and peritoneal fluid of women with deeply infiltrating pelvic endometriosis. , 1992, Fertility and sterility.

[4]  L. Giudice Genomics' Role in Understanding the Pathogenesis of Endometriosis , 2003, Seminars in reproductive medicine.

[5]  Tsuyoshi Saito,et al.  Over‐expression of heat shock proteins in carcinogenic endometrium , 2001, International journal of cancer.

[6]  G. Downey,et al.  Role of the actin cytoskeleton in insulin action , 1999, Microscopy research and technique.

[7]  F. Penault-Llorca,et al.  DNA microarray analysis of gene expression profiles in deep endometriosis using laser capture microdissection. , 2004, Molecular human reproduction.

[8]  N. Bulleid,et al.  Oxidative protein folding in the mammalian endoplasmic reticulum. , 2004, Biochemical Society transactions.

[9]  J. Squifflet,et al.  Current Thinking on the Pathogenesis of Endometriosis , 2002, Gynecologic and Obstetric Investigation.

[10]  L. Ruddock,et al.  The human protein disulphide isomerase family: substrate interactions and functional properties , 2005, EMBO reports.

[11]  Y. Kitaoka,et al.  Endometriosis: the pathophysiology as an estrogen-dependent disease , 2002, The Journal of Steroid Biochemistry and Molecular Biology.

[12]  P. Rogers,et al.  Recent advances in endometrial angiogenesis research , 2005, Angiogenesis.

[13]  A. Olivares,et al.  Basal and gonadotropin-releasing hormone-releasable serum follicle-stimulating hormone charge isoform distribution and in vitro biological-to-immunological ratio in male puberty , 2004, Endocrine.

[14]  B. Tom,et al.  Determination of the transcript profile of human endometrium. , 2003, Molecular human reproduction.

[15]  J. Yodoi,et al.  Induction of Thioredoxin, a Redox-Active Protein, by Ovarian Steroid Hormones during Growth and Differentiation of Endometrial Stromal Cells in Vitro* * This work was supported by a Grant-in-Aid for Scientific Research, Japan. , 1999, Endocrinology.

[16]  E. Wolf,et al.  Holistic differential analysis of embryo‐induced alterations in the proteome of bovine endometrium in the preattachment period , 2005, Proteomics.

[17]  Robert N. Taylor,et al.  Glycodelin: a major lipocalin protein of the reproductive axis with diverse actions in cell recognition and differentiation. , 2002, Endocrine reviews.

[18]  J. Stubbe,et al.  Ribonucleotide reductases: amazing and confusing. , 1990, The Journal of biological chemistry.

[19]  J. P. Yang,et al.  Expression profiling of endometrium from women with endometriosis reveals candidate genes for disease-based implantation failure and infertility. , 2003, Endocrinology.

[20]  Bonnie F. Sloane,et al.  Cathepsin B and its role(s) in cancer progression. , 2003, Biochemical Society symposium.

[21]  J. Brannian,et al.  DNA microarray analysis of gene expression markers of endometriosis. , 2002, Fertility and sterility.

[22]  L. Kiesel,et al.  Endometriosis: a genetic disease. , 2003, Drugs of today.

[23]  A. Arıcı,et al.  Effects of oxidants and antioxidants on proliferation of endometrial stromal cells. , 2004, Fertility and sterility.

[24]  S. Brennecke,et al.  Proteomic approaches in endometriosis research , 2004, Proteomics.

[25]  S. Isom,et al.  Regulation of Prohibitin Expression During Follicular Development and Atresia in the Mammalian Ovary1 , 2004, Biology of reproduction.

[26]  Michael Vernon,et al.  Changes in gene expression during the early to mid-luteal (receptive phase) transition in human endometrium detected by high-density microarray screening. , 2002, Molecular human reproduction.

[27]  A. Tsimberidou,et al.  Evolving role of ribonucleoside reductase inhibitors in hematologic malignancies , 2002, Expert review of anticancer therapy.

[28]  A. Holmgren,et al.  Immunohistochemical localization of glutaredoxin and thioredoxin in human endometrium: a possible association with pinopodes. , 2002, Molecular human reproduction.

[29]  Dae-Yeul Yu,et al.  Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II , 2005, Nature.

[30]  J. P. Yang,et al.  Global gene profiling in human endometrium during the window of implantation. , 2002, Endocrinology.

[31]  D. Spandidos,et al.  Microsatellite DNA assays reveal an allelic imbalance in p16(Ink4), GALT, p53, and APOA2 loci in patients with endometriosis. , 2001, Fertility and sterility.

[32]  C. Christiansen,et al.  Human endometrial proteins with cyclic changes in the expression during the normal menstrual cycle: characterization by protein sequence analysis , 1995 .

[33]  S. Chellappan,et al.  Prohibitin Induces the Transcriptional Activity of p53 and Is Exported from the Nucleus upon Apoptotic Signaling* , 2003, Journal of Biological Chemistry.

[34]  M. Vega,et al.  Augmented cell survival in eutopic endometrium from women with endometriosis: Expression of c-myc, TGF-beta1 and bax genes , 2005, Reproductive biology and endocrinology : RB&E.

[35]  M. Inagaki,et al.  Regulatory mechanisms and functions of intermediate filaments: A study using site‐ and phosphorylation state‐specific antibodies , 2006, Cancer science.

[36]  J. Yodoi,et al.  Thioredoxin expression in the human endometrium during the menstrual cycle. , 1997, Molecular human reproduction.

[37]  J. Schneider,et al.  c-myc, c-erb-B2, nm23 and p53 expression in human endometriosis. , 1998, Oncology reports.

[38]  M. Menger,et al.  Combined inhibition of vascular endothelial growth factor (VEGF), fibroblast growth factor and platelet-derived growth factor, but not inhibition of VEGF alone, effectively suppresses angiogenesis and vessel maturation in endometriotic lesions. , 2006, Human reproduction.

[39]  B. Huppertz,et al.  Regulation of functional steroid receptors and ligand-induced responses in telomerase-immortalized human endometrial epithelial cells. , 2005, Journal of molecular endocrinology.

[40]  C. Kyama,et al.  Future Directions in Endometriosis Research , 2004, Annals of the New York Academy of Sciences.

[41]  J. Donnez,et al.  Potential involvement of hemoglobin and heme in the pathogenesis of peritoneal endometriosis. , 2002, Fertility and sterility.

[42]  S. Futaki,et al.  Enzymatic activation of immunoglobulin binding factor in female reproductive tract. , 1998, Biochemical and biophysical research communications.

[43]  C. Schneeberger,et al.  Ten Estrogen-Related Polymorphisms and Endometriosis: A Study of Multiple Gene–Gene Interactions , 2005, Obstetrics and gynecology.

[44]  C. Huck,et al.  Biomarker discovery in breast cancer serum using 2‐D differential gel electrophoresis/ MALDI‐TOF/TOF and data validation by routine clinical assays , 2006, Electrophoresis.

[45]  C. Christiansen,et al.  Two-dimensional gel analysis of human endometrial proteins: cyclic changes in the expression of specific proteins during the normal menstrual cycle. , 1995, Human reproduction.

[46]  C. Simón,et al.  Gene expression profiling of human endometrial receptivity on days LH+2 versus LH+7 by microarray technology. , 2003, Molecular human reproduction.

[47]  E. Dreher,et al.  PAPP-A and osteoprotegerin, together with interleukin-8 and RANTES, are elevated in the peritoneal fluid of women with endometriosis. , 2006, American journal of obstetrics and gynecology.

[48]  E. Vuorio,et al.  Expression patterns of cathepsins B, H, K, L and S in the human endometrium. , 2001, Molecular human reproduction.

[49]  A. Asumendi,et al.  Role of cytoskeleton in apoptosis. , 2000, Vitamins and hormones.

[50]  P. Cash,et al.  Growth‐induced changes in the proteome of Helicobacter pylori , 2006, Electrophoresis.

[51]  R. Taylor The future of endometriosis research: genomics and proteomics? , 2004, Gynecologic and obstetric investigation.

[52]  K. L. Sharpe-Timms,et al.  Endometrial Anomalies in Women with Endometriosis , 2001, Annals of the New York Academy of Sciences.

[53]  C. Christiansen,et al.  Two-dimensional gel analysis of human endometrial proteins: characterization of proteins with increased expression in hyperplasia and adenocarcinoma. , 1999, Molecular human reproduction.

[54]  D. Edmonds,et al.  Elevated Serum Lipoprotein(a) Levels in Young Women With Endometriosis , 1997 .

[55]  N. Haites,et al.  Human fetal testis: second trimester proliferative and steroidogenic capacities. , 2000, The Journal of clinical endocrinology and metabolism.

[56]  J. Hatazawa,et al.  Distribution of heat shock proteins in eutopic and ectopic endometrium in endometriosis and adenomyosis. , 1997, Fertility and sterility.

[57]  S. Rhee,et al.  Peroxiredoxins: a historical overview and speculative preview of novel mechanisms and emerging concepts in cell signaling. , 2005, Free radical biology & medicine.

[58]  N. Nagaraj,et al.  Silencing of cystatin M in metastatic oral cancer cell line MDA-686Ln by siRNA increases cysteine proteinases and legumain activities, cell proliferation and in vitro invasion. , 2006, Life sciences.

[59]  E. Vuorio,et al.  Altered expression of genes involved in the production and degradation of endometrial extracellular matrix in patients with unexplained infertility and recurrent miscarriages. , 2002, Molecular human reproduction.