Skip to main content

Advertisement

Log in

Molecular mechanisms underlying endometriosis pathogenesis revealed by bioinformatics analysis of microarray data

  • General Gynecology
  • Published:
Archives of Gynecology and Obstetrics Aims and scope Submit manuscript

Abstract

Objective

To identify differentially expressed genes (DEGs) in endometriosis and further analyze molecular mechanisms implicated in disease pathogenesis.

Materials and methods

Gene expression data (ID: GSE7846) of human endometrial endothelial cells (HEECs) collected from eutopic endometria tissue of patients with and without endometriosis were downloaded from Gene Expression Omnibus. DEGs were screened using Limma package, followed by enrichment analysis using clusterProfiler package in R. Thereafter, protein–protein interactions (PPIs) were analyzed using STRING (Search Tool for the Retrieval of Interacting Genes) database and visualized by Cytoscape software. Meanwhile, transcription factors were screened from the DEGs based on TRANSFA database, followed by construction of regulatory network using Cytoscape.

Results

A total of 2255 up- and 408 down-regulated genes were identified in endometriosis patients as compared with control patients. Those DEGs were predominantly enriched in focal adhesion (e.g., FN1, EGF, FYN, EGFR, RAC1, CCND1 and JUN), regulation of actin cytoskeleton (e.g., FN1, EGF, EGFR, RAC1 and JUN) and MAPK signaling pathway (e.g., EGF, EGFR, RAC1, JUN, TGFB1 and MYC). Importantly, EGF, EGFR, JUN, FN1, RAC1, TGFB1, CCND1 and FYN were hub nodes in the PPI network. Additionally, TGFB1, SMAD1 and SMAD4 showed up-regulation in TGFB signaling pathway. Transcription factor MYC had a regulatory effect on the most DEGs, including TGFB1, RAC1 and CCND1.

Conclusions

Focal adhesion, regulation of actin cytoskeleton, MAPK and TGFB/SMAD signaling pathway may be important molecular mechanism underlying the pathogenesis of endometriosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Cramer DW, Missmer SA (2002) The epidemiology of endometriosis. Ann N Y Acad Sci 955(1):11–22

    Article  PubMed  Google Scholar 

  2. Kobayashi H, Kajihara H, Yamada Y, Tanase Y, Kanayama S, Furukawa N, Noguchi T, Haruta S, Yoshida S, Naruse K, Sado T, Oi H (2011) Risk of carcinoma in women with ovarian endometrioma. Front Biosci 3:529–539

    Article  Google Scholar 

  3. Vercellini P, Vigano P, Somigliana E, Fedele L (2014) Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 10(5):261–275. doi:10.1038/nrendo.2013.255

    Article  CAS  PubMed  Google Scholar 

  4. Kobayashi H, Imanaka S, Nakamura H, Tsuji A (2014) Understanding the role of epigenomic, genomic and genetic alterations in the development of endometriosis (review). Mol Med Rep 9(5):1483–1505. doi:10.3892/mmr.2014.2057

    CAS  PubMed  Google Scholar 

  5. Burney RO, Talbi S, Hamilton AE, Vo KC, Nyegaard M, Nezhat CR, Lessey BA, Giudice LC (2007) Gene expression analysis of endometrium reveals progesterone resistance and candidate susceptibility genes in women with endometriosis. Endocrinology 148(8):3814–3826. doi:10.1210/en.2006-1692

    Article  CAS  PubMed  Google Scholar 

  6. Baranov VS, Ivaschenko TE, Liehr T, Yarmolinskaya MI (2014) Systems genetics view of endometriosis: a common complex disorder. Eur J Obstet Gynecol Reprod Biol 185c:59–65. doi:10.1016/j.ejogrb.2014.11.036

    Google Scholar 

  7. Khan MA, Sengupta J, Mittal S, Ghosh D (2012) Genome-wide expressions in autologous eutopic and ectopic endometrium of fertile women with endometriosis. Reprod Biol Endocrinol RB&E 10:84. doi:10.1186/1477-7827-10-84

    Article  CAS  Google Scholar 

  8. Samartzis N, Samartzis EP, Noske A, Fedier A, Dedes KJ, Caduff R, Fink D, Imesch P (2012) Expression of the G protein-coupled estrogen receptor (GPER) in endometriosis: a tissue microarray study. Reprod Biol Endocrinol RB&E 10:30. doi:10.1186/1477-7827-10-30

    Article  CAS  Google Scholar 

  9. Sha G, Wu D, Zhang L, Chen X, Lei M, Sun H, Lin S, Lang J (2007) Differentially expressed genes in human endometrial endothelial cells derived from eutopic endometrium of patients with endometriosis compared with those from patients without endometriosis. Human Reprod 22(12):3159–3169. doi:10.1093/humrep/dem266

    Article  CAS  Google Scholar 

  10. Altermann E, Klaenhammer TR (2005) PathwayVoyager: pathway mapping using the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. BMC Genom 6:60. doi:10.1186/1471-2164-6-60

    Article  Google Scholar 

  11. Franceschini A, Szklarczyk D, Frankild S, Kuhn M, Simonovic M, Roth A, Lin J, Minguez P, Bork P, von Mering C (2013) STRING v9. 1: protein-protein interaction networks, with increased coverage and integration. Nucleic Acids Res 41(D1):D808–D815

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Li C, Wong WH (2003) DNA-chip analyzer (dChip). In: The Analysis of Gene Expression Data. Springer, pp 120–141

  13. Smyth GK (2005) Limma: linear models for microarray data. In: Bioinformatics and computational biology solutions using R and Bioconductor. Springer, pp 397–420

  14. Yu G, Wang LG, Han Y, He QY (2012) clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS 16(5):284–287. doi:10.1089/omi.2011.0118

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kohl M, Wiese S, Warscheid B (2011) Cytoscape: software for visualization and analysis of biological networks. In: Data Mining in Proteomics. Springer, pp 291–303

  16. Matys V, Fricke E, Geffers R, Gößling E, Haubrock M, Hehl R, Hornischer K, Karas D, Kel AE, Kel-Margoulis OV (2003) TRANSFAC®: transcriptional regulation, from patterns to profiles. Nucleic Acids Res 31(1):374–378

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Romer LH, Birukov KG, Garcia JG (2006) Focal adhesions: paradigm for a signaling nexus. Circ Res 98(5):606–616. doi:10.1161/01.RES.0000207408.31270.db

    Article  CAS  PubMed  Google Scholar 

  18. Pagliardini L, Gentilini D, Vigano P, Panina-Bordignon P, Busacca M, Candiani M, Di Blasio AM (2013) An Italian association study and meta-analysis with previous GWAS confirm WNT4, CDKN2BAS and FN1 as the first identified susceptibility loci for endometriosis. J Med Genet 50(1):43–46. doi:10.1136/jmedgenet-2012-101257

    Article  CAS  PubMed  Google Scholar 

  19. An L, Song L, Zhang W, Lu X, Chen S, Zhao S (2014) The aspartic acid of Fyn at 390 is critical for neuronal migration during corticogenesis. Exp Cell Res 328(2):419–428. doi:10.1016/j.yexcr.2014.09.012

    Article  CAS  PubMed  Google Scholar 

  20. Teutschbein J, Schartl M, Meierjohann S (2009) Interaction of Xiphophorus and murine Fyn with focal adhesion kinase. Comp Biochem Physiol Toxicol Pharmacol CBP 149(2):168–174. doi:10.1016/j.cbpc.2008.09.013

    Article  Google Scholar 

  21. Radulovich N, Pham NA, Strumpf D, Leung L, Xie W, Jurisica I, Tsao MS (2010) Differential roles of cyclin D1 and D3 in pancreatic ductal adenocarcinoma. Mol Cancer 9:24. doi:10.1186/1476-4598-9-24

    Article  PubMed  PubMed Central  Google Scholar 

  22. Chikano Y, Domoto T, Furuta T, Sabit H, Kitano-Tamura A, Pyko IV, Takino T, Sai Y, Hayashi Y, Sato H, Miyamoto KI, Nakada M, Minamoto T (2014) Glycogen synthase kinase 3beta sustains invasion of glioblastoma via the focal adhesion kinase, Rac1 and c-Jun N-terminal kinase-mediated pathway. Mol Cancer Ther. doi:10.1158/1535-7163.mct-14-0479

    PubMed  Google Scholar 

  23. Flamini MI, Sanchez AM, Goglia L, Tosi V, Genazzani AR, Simoncini T (2009) Differential actions of estrogen and SERMs in regulation of the actin cytoskeleton of endometrial cells. Mol Hum Reprod 15(10):675–685. doi:10.1093/molehr/gap045

    Article  CAS  PubMed  Google Scholar 

  24. Hutcheson IR, Knowlden JM, Madden TA, Barrow D, Gee JM, Wakeling AE, Nicholson RI (2003) Oestrogen receptor-mediated modulation of the EGFR/MAPK pathway in tamoxifen-resistant MCF-7 cells. Breast Cancer Res Treat 81(1):81–93. doi:10.1023/a:1025484908380

    Article  CAS  PubMed  Google Scholar 

  25. Flevaris P, Li Z, Zhang G, Zheng Y, Liu J, Du X (2009) Two distinct roles of mitogen-activated protein kinases in platelets and a novel Rac1-MAPK-dependent integrin outside-in retractile signaling pathway. Blood 113(4):893–901. doi:10.1182/blood-2008-05-155978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Schenken RS, Johnson JV, Riehl RM (1991) c-myc protooncogene polypeptide expression in endometriosis. Am J Obstet Gynecol 164 (4):1031–1036 (discussion 1036–1037)

  27. Abe W, Nasu K, Nakada C, Kawano Y, Moriyama M, Narahara H (2013) miR-196b targets c-myc and Bcl-2 expression, inhibits proliferation and induces apoptosis in endometriotic stromal cells. Hum Reprod 28(3):750–761. doi:10.1093/humrep/des446

    Article  CAS  PubMed  Google Scholar 

  28. Yoshino O, Osuga Y, Hirota Y, Koga K, Hirata T, Harada M, Morimoto C, Yano T, Nishii O, Tsutsumi O (2004) Possible pathophysiological roles of mitogen-activated protein kinases (MAPKs) in endometriosis. Am J Reprod Immunol 52(5):306–311

    Article  PubMed  Google Scholar 

  29. Xie R, Schlumbrecht MP, Shipley GL, Xie S, Bassett RL, Broaddus RR (2009) S100A4 mediates endometrial cancer invasion and is a target of TGF-β1 signaling. Lab Invest 89(8):937–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Luo X, Xu J, Chegini N (2003) The expression of Smads in human endometrium and regulation and induction in endometrial epithelial and stromal cells by transforming growth factor-beta. J Clin Endocrinol Metab 88(10):4967–4976. doi:10.1210/jc.2003-030276

    Article  CAS  PubMed  Google Scholar 

  31. Saito A, Osuga Y, Yoshino O, Takamura M, Hirata T, Hirota Y, Koga K, Harada M, Takemura Y, Yano T (2011) TGF-β1 induces proteinase-activated receptor 2 (PAR2) expression in endometriotic stromal cells and stimulates PAR2 activation-induced secretion of IL-6. Hum Reprod 26(7):1892–1898

    Article  CAS  PubMed  Google Scholar 

  32. Kobayashi H, Yamada Y, Morioka S, Niiro E, Shigemitsu A, Ito F (2014) Mechanism of pain generation for endometriosis-associated pelvic pain. Arch Gynecol Obstet 289(1):13–21

    Article  CAS  PubMed  Google Scholar 

  33. Zevallos HB-V, McKinnon B, Tokushige N, Mueller MD, Fraser IS, Bersinger NA (2015) Detection of the pan neuronal marker PGP9. 5 by immuno-histochemistry and quantitative PCR in eutopic endometrium from women with and without endometriosis. Arch Gynecol Obstet 291(1):85–91

    Article  CAS  PubMed  Google Scholar 

  34. Meibody FA, Kashi AM, Mirzaie AZ, Amam MGB, Behbahani AS, Zolali B, Najafi L (2011) Diagnosis of endometrial nerve fibers in women with endometriosis. Arch Gynecol Obstet 284(5):1157–1162

    Article  Google Scholar 

  35. Anaf V, Simon P, El Nakadi I, Fayt I, Simonart T, Buxant F, Noël JC (2002) Hyperalgesia, nerve infiltration and nerve growth factor expression in deep adenomyotic nodules, peritoneal and ovarian endometriosis. Hum Reprod 17(7):1895–1900

    Article  PubMed  Google Scholar 

  36. Noël J-C, Chapron C, Fayt I, Anaf V (2008) Lymph node involvement and lymphovascular invasion in deep infiltrating rectosigmoid endometriosis. Fertil Steril 89(5):1069–1072

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shengmin Ping.

Ethics declarations

Conflict of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ping, S., Ma, C., Liu, P. et al. Molecular mechanisms underlying endometriosis pathogenesis revealed by bioinformatics analysis of microarray data. Arch Gynecol Obstet 293, 797–804 (2016). https://doi.org/10.1007/s00404-015-3875-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00404-015-3875-y

Keywords

Navigation