Advertisement

Archives of Gynecology and Obstetrics

, Volume 297, Issue 5, pp 1323–1332 | Cite as

Identification of key genes and pathways in pelvic organ prolapse based on gene expression profiling by bioinformatics analysis

  • Quan Zhou
  • Li Hong
  • Jing Wang
Urogynecology
  • 201 Downloads

Abstract

Purpose

The aim of this study was to elucidate the molecular mechanisms and to identify the key genes and pathways for pelvic organ prolapse (POP) using bioinformatics analysis.

Methods

The microarray data for GSE53868 included 12 POP and 12 non-POP anterior vaginal wall samples. Differentially expressed genes (DEGs) were identified by GEO2R online tool. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the DAVID database, and a DEG-associated protein–protein interaction (PPI) network was constructed using STRING and visualized in Cytoscape. MCODE was used for module analysis of the PPI network.

Results

A total of 257 upregulated and 333 downregulated genes were identified. GO and KEGG pathway enrichment analyses showed that the upregulated DEGs were strongly associated with immune response, complement activation, classical pathway, phagocytosis, and recognition; the downregulated genes were mainly associated with cellular response to zinc ion, negative regulation of growth, and apoptotic process. Based on the PPI network, IL6, MYC, CCL2, ICAM1, PTGS2, SERPINE1, ATF3, CDKN1A, and CDKN2A were screened as hub genes. The four most significant sub-modules of DEGs were extracted after network module analysis. These genes were mainly associated with the negative regulation of growth and inflammatory response. The KEGG pathway enrichment analysis revealed that these genes were associated with Mineral absorption, Jak-STAT signaling pathway, cytokine–cytokine receptor interaction, and chemokine signaling pathway.

Conclusions

These microarray data and bioinformatics analyses provide a useful method for the identification of key genes and pathways associated with POP. Moreover, some crucial DEGs, such as IL6, MYC, CCL2, ICAM1, PTGS2, SERPINE1, ATF3, CDKN1A, and CDKN2A, potentially play an important role in the development and progression of POP.

Keywords

Pelvic organ prolapse Gene expression profiling Bioinformatics analysis Differentially expressed genes 

Notes

Author contributions

QZ: project development, data collection, manuscript writing, and data analysis. LH: project development, data collection, and manuscript editing. JW: manuscript writing and data analysis.

Funding

This study was funded by National Natural Science Foundation of China (No. 81401187).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

This article does not contain any studies with human reporters or animals performed by any of the authors.

References

  1. 1.
    Nygaard I, Barber MD, Burgio KL, Kenton K, Meikle S, Schaffer J, Spino C, Whitehead WE, Wu J, Brody DJ, Pelvic Floor Disorders N (2008) Prevalence of symptomatic pelvic floor disorders in US women. JAMA 300(11):1311–1316.  https://doi.org/10.1001/jama.300.11.1311 CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Nygaard IE, Shaw JM, Bardsley T, Egger MJ (2014) Lifetime physical activity and pelvic organ prolapse in middle-aged women. Am J Obstet Gynecol 210(5):477.  https://doi.org/10.1016/j.ajog.2014.01.035 (e471–412) CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Olsen AL, Smith VJ, Bergstrom JO, Colling JC, Clark AL (1997) Epidemiology of surgically managed pelvic organ prolapse and urinary incontinence. Obstet Gynecol 89(4):501–506.  https://doi.org/10.1016/S0029-7844(97)00058-6 CrossRefPubMedGoogle Scholar
  4. 4.
    Clark AL, Gregory T, Smith VJ, Edwards R (2003) Epidemiologic evaluation of reoperation for surgically treated pelvic organ prolapse and urinary incontinence. Am J Obstet Gynecol 189(5):1261–1267CrossRefPubMedGoogle Scholar
  5. 5.
    Vergeldt TF, Weemhoff M, IntHout J, Kluivers KB (2015) Risk factors for pelvic organ prolapse and its recurrence: a systematic review. Int Urogynecol J 26(11):1559–1573.  https://doi.org/10.1007/s00192-015-2695-8 CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Ward RM, Velez Edwards DR, Edwards T, Giri A, Jerome RN, Wu JM (2014) Genetic epidemiology of pelvic organ prolapse: a systematic review. Am J Obstet Gynecol 211(4):326–335.  https://doi.org/10.1016/j.ajog.2014.04.006 CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Lince SL, van Kempen LC, Vierhout ME, Kluivers KB (2012) A systematic review of clinical studies on hereditary factors in pelvic organ prolapse. Int Urogynecol J 23(10):1327–1336.  https://doi.org/10.1007/s00192-012-1704-4 CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Cartwright R, Kirby AC, Tikkinen KA, Mangera A, Thiagamoorthy G, Rajan P, Pesonen J, Ambrose C, Gonzalez-Maffe J, Bennett P, Palmer T, Walley A, Jarvelin MR, Chapple C, Khullar V (2015) Systematic review and metaanalysis of genetic association studies of urinary symptoms and prolapse in women. Am J Obstet Gynecol 212(2):199.  https://doi.org/10.1016/j.ajog.2014.08.005 (e191–124) CrossRefPubMedPubMedCentralGoogle Scholar
  9. 9.
    Rodrigues AM, Girao MJ, da Silva ID, Sartori MG, Martins Kde F, Castro Rde A (2008) COL1A1 Sp1-binding site polymorphism as a risk factor for genital prolapse. Int Urogynecol J Pelvic Floor Dysfunct 19(11):1471–1475.  https://doi.org/10.1007/s00192-008-0662-3 CrossRefPubMedGoogle Scholar
  10. 10.
    Lince SL, van Kempen LC, Dijkstra JR, IntHout J, Vierhout ME, Kluivers KB (2014) Collagen type III alpha 1 polymorphism (rs1800255, COL3A1 2209 G > A) assessed with high-resolution melting analysis is not associated with pelvic organ prolapse in the Dutch population. Int Urogynecol J 25(9):1237–1242.  https://doi.org/10.1007/s00192-014-2385-y CrossRefPubMedGoogle Scholar
  11. 11.
    Kluivers KB, Dijkstra JR, Hendriks JC, Lince SL, Vierhout ME, van Kempen LC (2009) COL3A1 2209G > A is a predictor of pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct 20(9):1113–1118.  https://doi.org/10.1007/s00192-009-0913-y CrossRefPubMedGoogle Scholar
  12. 12.
    Jeon MJ, Chung SM, Choi JR, Jung HJ, Kim SK, Bai SW (2009) The relationship between COL3A1 exon 31 polymorphism and pelvic organ prolapse. J Urol 181(3):1213–1216.  https://doi.org/10.1016/j.juro.2008.11.027 CrossRefPubMedGoogle Scholar
  13. 13.
    Chen HY, Chung YW, Lin WY, Wang JC, Tsai FJ, Tsai CH (2008) Collagen type 3 alpha 1 polymorphism and risk of pelvic organ prolapse. Int J Gynaecol Obstet Off Organ Int Fed Gynaecol Obstet 103(1):55–58.  https://doi.org/10.1016/j.ijgo.2008.05.031 CrossRefGoogle Scholar
  14. 14.
    Ferrari MM, Rossi G, Biondi ML, Vigano P, Dell’utri C, Meschia M (2012) Type I collagen and matrix metalloproteinase 1, 3 and 9 gene polymorphisms in the predisposition to pelvic organ prolapse. Arch Gynecol Obstet 285(6):1581–1586.  https://doi.org/10.1007/s00404-011-2199-9 CrossRefPubMedGoogle Scholar
  15. 15.
    Wu JM, Visco AG, Grass EA, Craig DM, Fulton RG, Haynes C, Amundsen CL, Shah SH (2012) Comprehensive analysis of LAMC1 genetic variants in advanced pelvic organ prolapse. Am J Obstet Gynecol 206(5):447.  https://doi.org/10.1016/j.ajog.2012.01.033 (e441–446) CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Nikolova G, Lee H, Berkovitz S, Nelson S, Sinsheimer J, Vilain E, Rodriguez LV (2007) Sequence variant in the laminin gamma1 (LAMC1) gene associated with familial pelvic organ prolapse. Hum Genet 120(6):847–856.  https://doi.org/10.1007/s00439-006-0267-1 CrossRefPubMedGoogle Scholar
  17. 17.
    Chen C, Hill LD, Schubert CM, Strauss JF 3rd, Matthews CA (2010) Is laminin gamma-1 a candidate gene for advanced pelvic organ prolapse? Am J Obstet Gynecol 202(5):505.  https://doi.org/10.1016/j.ajog.2010.01.014 (e501–505) CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Moon YJ, Bai SW, Jung CY, Kim CH (2013) Estrogen-related genome-based expression profiling study of uterosacral ligaments in women with pelvic organ prolapse. Int Urogynecol J 24(11):1961–1967.  https://doi.org/10.1007/s00192-013-2124-9 CrossRefPubMedGoogle Scholar
  19. 19.
    Chen HY, Chung YW, Lin WY, Chen WC, Tsai FJ, Tsai CH (2008) Estrogen receptor alpha polymorphism is associated with pelvic organ prolapse risk. Int Urogynecol J Pelvic Floor dysfunct 19(8):1159–1163.  https://doi.org/10.1007/s00192-008-0603-1 CrossRefPubMedGoogle Scholar
  20. 20.
    Chen HY, Chung YW, Lin WY, Chen WC, Tsai FJ, Tsai CH (2009) Progesterone receptor polymorphism is associated with pelvic organ prolapse risk. Acta Obstet Gynecol Scand 88(7):835–838.  https://doi.org/10.1080/00016340902822073 CrossRefPubMedGoogle Scholar
  21. 21.
    Bai SW, Chung DJ, Yoon JM, Shin JS, Kim SK, Park KH (2005) Roles of estrogen receptor, progesterone receptor, p53 and p21 in pathogenesis of pelvic organ prolapse. Int Urogynecol J Pelvic Floor Dysfunct 16(6):492–496.  https://doi.org/10.1007/s00192-005-1310-9 CrossRefPubMedGoogle Scholar
  22. 22.
    Allen-Brady K, Norton PA, Farnham JM, Teerlink C, Cannon-Albright LA (2009) Significant linkage evidence for a predisposition gene for pelvic floor disorders on chromosome 9q21. Am J Hum Genet 84(5):678–682.  https://doi.org/10.1016/j.ajhg.2009.04.002 CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Allen-Brady K, Cannon-Albright LA, Farnham JM, Norton PA (2015) Evidence for pelvic organ prolapse predisposition genes on chromosomes 10 and 17. Am J Obstet Gynecol 212(6):771.  https://doi.org/10.1016/j.ajog.2014.12.037 (e771–777) CrossRefPubMedGoogle Scholar
  24. 24.
    Khadzhieva MB, Kolobkov DS, Kamoeva SV, Ivanova AV, Abilev SK, Salnikova LE (2015) Verification of the chromosome region 9q21 association with pelvic organ prolapse using RegulomeDB annotations. Biomed Res Int 2015:837904.  https://doi.org/10.1155/2015/837904 CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Couri BM, Borazjani A, Lenis AT, Balog B, Kuang M, Lin DL, Damaser MS (2014) Validation of genetically matched wild-type strain and lysyl oxidase-like 1 knockout mouse model of pelvic organ prolapse. Female Pelvic Med Reconstr Surg 20(5):287–292.  https://doi.org/10.1097/SPV.0000000000000104 CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Drewes PG, Yanagisawa H, Starcher B, Hornstra I, Csiszar K, Marinis SI, Keller P, Word RA (2007) Pelvic organ prolapse in fibulin-5 knockout mice: pregnancy-induced changes in elastic fiber homeostasis in mouse vagina. Am J Pathol 170(2):578–589.  https://doi.org/10.2353/ajpath.2007.060662 CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Chin K, Wieslander C, Shi H, Balgobin S, Montoya TI, Yanagisawa H, Word RA (2016) Pelvic organ support in animals with partial loss of fibulin-5 in the vaginal wall. PLoS One 11(4):e0152793.  https://doi.org/10.1371/journal.pone.0152793 CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Rahn DD, Acevedo JF, Roshanravan S, Keller PW, Davis EC, Marmorstein LY, Word RA (2009) Failure of pelvic organ support in mice deficient in fibulin-3. Am J Pathol 174(1):206–215.  https://doi.org/10.2353/ajpath.2009.080212 CrossRefPubMedPubMedCentralGoogle Scholar
  29. 29.
    Connell KA, Guess MK, Chen H, Andikyan V, Bercik R, Taylor HS (2008) HOXA11 is critical for development and maintenance of uterosacral ligaments and deficient in pelvic prolapse. J Clin Investig 118(3):1050–1055.  https://doi.org/10.1172/JCI34193 PubMedPubMedCentralGoogle Scholar
  30. 30.
    Ma Y, Guess M, Datar A, Hennessey A, Cardenas I, Johnson J, Connell KA (2012) Knockdown of Hoxa11 in vivo in the uterosacral ligament and uterus of mice results in altered collagen and matrix metalloproteinase activity. Biol Reprod 86(4):100.  https://doi.org/10.1095/biolreprod.111.093245 CrossRefPubMedGoogle Scholar
  31. 31.
    Angarica VE, Del Sol A (2017) Bioinformatics tools for genome-wide epigenetic research. Adv Exp Med Biol 978:489–512.  https://doi.org/10.1007/978-3-319-53889-1_25 CrossRefPubMedGoogle Scholar
  32. 32.
    Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, Marshall KA, Phillippy KH, Sherman PM, Holko M, Yefanov A, Lee H, Zhang N, Robertson CL, Serova N, Davis S, Soboleva A (2013) NCBI GEO: archive for functional genomics data sets-update. Nucleic Acids Res 41(Database issue):D991–D995.  https://doi.org/10.1093/nar/gks1193 PubMedGoogle Scholar
  33. 33.
    Gene Ontology C (2006) The Gene Ontology (GO) project in 2006. Nucleic Acids Res 34(Database issue):D322–D326.  https://doi.org/10.1093/nar/gkj021 CrossRefGoogle Scholar
  34. 34.
    Kanehisa M, Goto S (2000) KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res 28(1):27–30CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Fernandes MT, Fernandes KB, Marquez AS, Colus IM, Souza MF, Santos JP, Poli-Frederico RC (2015) Association of interleukin-6 gene polymorphism (rs1800796) with severity and functional status of osteoarthritis in elderly individuals. Cytokine 75(2):316–320.  https://doi.org/10.1016/j.cyto.2015.07.020 CrossRefPubMedGoogle Scholar
  36. 36.
    Kaminski KA, Oledzka E, Bialobrzewska K, Kozuch M, Musial WJ, Winnicka MM (2007) The effects of moderate physical exercise on cardiac hypertrophy in interleukin 6 deficient mice. Adv Med Sci 52:164–168PubMedGoogle Scholar
  37. 37.
    Moller AB, Vendelbo MH, Rahbek SK, Clasen BF, Schjerling P, Vissing K, Jessen N (2013) Resistance exercise, but not endurance exercise, induces IKKbeta phosphorylation in human skeletal muscle of training-accustomed individuals. Pflugers Arch 465(12):1785–1795.  https://doi.org/10.1007/s00424-013-1318-9 CrossRefPubMedGoogle Scholar
  38. 38.
    Kalkat M, De Melo J, Hickman KA, Lourenco C, Redel C, Resetca D, Tamachi A, Tu WB, Penn LZ (2017) MYC deregulation in primary human cancers. Genes.  https://doi.org/10.3390/genes8060151 PubMedPubMedCentralGoogle Scholar
  39. 39.
    da Chung J, Bai SW (2006) Roles of sex steroid receptors and cell cycle regulation in pathogenesis of pelvic organ prolapse. Curr Opin Obstet Gynecol 18(5):551–554.  https://doi.org/10.1097/01.gco.0000242959.63362.1e CrossRefGoogle Scholar
  40. 40.
    Hubal MJ, Devaney JM, Hoffman EP, Zambraski EJ, Gordish-Dressman H, Kearns AK, Larkin JS, Adham K, Patel RR, Clarkson PM (2010) CCL2 and CCR2 polymorphisms are associated with markers of exercise-induced skeletal muscle damage. J Appl Physiol 108(6):1651–1658.  https://doi.org/10.1152/japplphysiol.00361.2009 CrossRefPubMedGoogle Scholar
  41. 41.
    Gay AN, Mushin OP, Lazar DA, Naik-Mathuria BJ, Yu L, Gobin A, Smith CW, Olutoye OO (2011) Wound healing characteristics of ICAM-1 null mice devoid of all isoforms of ICAM-1. J Surg Res 171(1):e1–e7.  https://doi.org/10.1016/j.jss.2011.06.053 CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Byeseda SE, Burns AR, Dieffenbaugher S, Rumbaut RE, Smith CW, Li Z (2009) ICAM-1 is necessary for epithelial recruitment of gammadelta T cells and efficient corneal wound healing. Am J Pathol 175(2):571–579.  https://doi.org/10.2353/ajpath.2009.090112 CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Feng J, Anderson K, Liu Y, Singh AK, Ehsan A, Sellke FW (2017) Cyclooxygenase 2 contributes to bradykinin-induced microvascular responses in peripheral arterioles after cardiopulmonary bypass. J Surg Res 218:246–252.  https://doi.org/10.1016/j.jss.2017.05.086 CrossRefPubMedGoogle Scholar
  44. 44.
    Lv X, Cai Z, Li S (2016) Increased apoptosis rate of human decidual cells and cytotrophoblasts in patients with recurrent spontaneous abortion as a result of abnormal expression of CDKN1A and Bax. Exp Ther Med 12(5):2865–2868.  https://doi.org/10.3892/etm.2016.3692 CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Al-Saran N, Subash-Babu P, Al-Nouri DM, Alfawaz HA, Alshatwi AA (2016) Zinc enhances CDKN2A, pRb1 expression and regulates functional apoptosis via upregulation of p53 and p21 expression in human breast cancer MCF-7 cell. Environ Toxicol Pharmacol 47:19–27.  https://doi.org/10.1016/j.etap.2016.08.002 CrossRefPubMedGoogle Scholar
  46. 46.
    Bond J, Adams S, Richards S, Vora A, Mitchell C, Goulden N (2011) Polymorphism in the PAI-1 (SERPINE1) gene and the risk of osteonecrosis in children with acute lymphoblastic leukemia. Blood 118(9):2632–2633.  https://doi.org/10.1182/blood-2011-05-355206 CrossRefPubMedGoogle Scholar
  47. 47.
    Wang Z, He Y, Deng W, Lang L, Yang H, Jin B, Kolhe R, Ding HF, Zhang J, Hai T, Yan C (2017) Atf3 deficiency promotes genome instability and spontaneous tumorigenesis in mice. Oncogene.  https://doi.org/10.1038/onc.2017.310 Google Scholar
  48. 48.
    Visco AG, Yuan L (2003) Differential gene expression in pubococcygeus muscle from patients with pelvic organ prolapse. Am J Obstet Gynecol 189(1):102–112CrossRefPubMedGoogle Scholar
  49. 49.
    Brizzolara SS, Killeen J, Urschitz J (2009) Gene expression profile in pelvic organ prolapse. Mol Hum Reprod 15(1):59–67.  https://doi.org/10.1093/molehr/gan074 CrossRefPubMedGoogle Scholar
  50. 50.
    Tseng LH, Chen I, Lin YH, Chen MY, Lo TS, Lee CL (2010) Genome-based expression profiles study for the pathogenesis of pelvic organ prolapse: an array of 33 genes model. Int Urogynecol J 21(1):79–84.  https://doi.org/10.1007/s00192-009-0990-y CrossRefPubMedGoogle Scholar
  51. 51.
    Dai YX, Lang JH, Zhu L, Liu ZF, Pan LY, Sun DW (2010) Microarray analysis of gene expression profiles in pelvic organ prolapse. Zhonghua Fu Chan Ke Za Zhi 45(5):342–347PubMedGoogle Scholar
  52. 52.
    Wang X, Li Y, Chen J, Guo X, Guan H, Li C (2014) Differential expression profiling of matrix metalloproteinases and tissue inhibitors of metalloproteinases in females with or without pelvic organ prolapse. Mol Med Rep 10(4):2004–2008.  https://doi.org/10.3892/mmr.2014.2467 CrossRefPubMedGoogle Scholar
  53. 53.
    Ak H, Zeybek B, Atay S, Askar N, Akdemir A, Aydin HH (2016) Microarray gene expression analysis of uterosacral ligaments in uterine prolapse. Clin Biochem 49(16–17):1238–1242.  https://doi.org/10.1016/j.clinbiochem.2016.08.004 CrossRefPubMedGoogle Scholar
  54. 54.
    Xie R, Xu Y, Fan S, Song Y (2016) Identification of differentially expressed genes in pelvic organ prolapse by RNA-Seq. Med Sci Monit Int Med J Exp Clin Res 22:4218–4225Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Gynecology and ObstetricsRenmin Hospital of Wuhan UniversityWuhanPeople’s Republic of China

Personalised recommendations