Identification of key genes and pathways in pelvic organ prolapse based on gene expression profiling by bioinformatics analysis
- 106 Downloads
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.
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.
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.
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.
KeywordsPelvic organ prolapse Gene expression profiling Bioinformatics analysis Differentially expressed genes
QZ: project development, data collection, manuscript writing, and data analysis. LH: project development, data collection, and manuscript editing. JW: manuscript writing and data analysis.
Compliance with ethical standards
Conflict of interest
The authors declare that they have no conflict of interest.
This article does not contain any studies with human reporters or animals performed by any of the authors.
- 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
- 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
- 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
- 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
- 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.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.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
- 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
- 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
- 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
- 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
- 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.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
- 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.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
- 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
- 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