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Archives of Gynecology and Obstetrics

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01-05-2018 | Urogynecology

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

Authors: Quan Zhou, Li Hong, Jing Wang

Published in: Archives of Gynecology and Obstetrics | Issue 5/2018

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.

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 CrossRefPubMedPubMedCentral

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) CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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):1261–1267CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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) CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRef

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 CrossRefPubMed

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) CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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) CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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) CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 PubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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 PubMed

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 CrossRef

34.

Kanehisa M, Goto S (2000) KEGG: Kyoto Encyclopedia of Genes and Genomes. Nucleic Acids Res 28(1):27–30CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 52:164–168PubMed

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 CrossRefPubMed

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 PubMedPubMedCentral

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 CrossRef

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMedPubMedCentral

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 CrossRefPubMed

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 CrossRefPubMed

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

48.

Visco AG, Yuan L (2003) Differential gene expression in pubococcygeus muscle from patients with pelvic organ prolapse. Am J Obstet Gynecol 189(1):102–112CrossRefPubMed

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 CrossRefPubMed

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 CrossRefPubMed

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):342–347PubMed

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 CrossRefPubMed

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 CrossRefPubMed

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 22:4218–4225

Title: Identification of key genes and pathways in pelvic organ prolapse based on gene expression profiling by bioinformatics analysis
Authors: Quan Zhou
Li Hong
Jing Wang
Publication date: 01-05-2018
Publisher: Springer Berlin Heidelberg
Published in: Archives of Gynecology and Obstetrics / Issue 5/2018
Print ISSN: 0932-0067
Electronic ISSN: 1432-0711
DOI: https://doi.org/10.1007/s00404-018-4745-1

At a glance: The STEP trials

Springer Medicine

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

Abstract

Purpose

Methods

Results

Conclusions

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusions

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