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Erschienen in: Medical Oncology 11/2016

01.11.2016 | Original Paper

Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis

verfasst von: Zhanzhan Xu, Yu Zhou, Yexuan Cao, Thi Lan Anh Dinh, Jing Wan, Min Zhao

Erschienen in: Medical Oncology | Ausgabe 11/2016

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Abstract

Ovarian cancer is the first leading cause of mortality in gynecological malignancies. To identify key genes and microRNAs in ovarian cancer, mRNA microarray dataset GSE36668, GSE18520, GSE14407 and microRNA dataset GSE47841 were downloaded from the Gene Expression Omnibus database. Differentially expressed genes (DEGs) and microRNAs (DEMs) were obtained using GEO2R. Functional and pathway enrichment analysis were performed for DEGs using DAVID database. Protein–protein interaction (PPI) network was established by STRING and visualized by Cytoscape. Following, overall survival (OS) analysis of hub genes was performed by the Kaplan–Meier plotter online tool. Module analysis of the PPI network was performed using MCODE. Moreover, miRecords was applied to predict the targets of the DEMs. A total of 345 DEGs were obtained, which were mainly enriched in the terms related to cell cycle, mitosis, and ovulation cycle process. A PPI network was constructed, consisting of 141 nodes and 296 edges. Sixteen genes had high degrees in the network. High expression of four genes of the 16 genes was associated with worse OS of patients with ovarian cancer, including CCNB1, CENPF, KIF11, and ZWINT. A significant module was detected from the PPI network. The enriched functions and pathways included cell cycle, nuclear division, and oocyte meiosis. Additionally, a total of 36 DEMs were identified. The expression of KIF11 was negatively correlated with that of has-miR-424 and has-miR-381, and it was also the potential target of two microRNAs. In conclusion, these results identified key genes, which could provide potential targets for ovarian cancer diagnosis and treatment.
Literatur
2.
4.
Zurück zum Zitat Goff BA, Mandel L, Muntz HG, Melancon CH. Ovarian carcinoma diagnosis. Cancer. 2000;89(10):2068–75.CrossRefPubMed Goff BA, Mandel L, Muntz HG, Melancon CH. Ovarian carcinoma diagnosis. Cancer. 2000;89(10):2068–75.CrossRefPubMed
7.
Zurück zum Zitat Vathipadiekal V, Wang V, Wei W, Waldron L, Drapkin R, Gillette M, et al. Creation of a human secretome: a novel composite library of human secreted proteins—validation using ovarian cancer gene expression data and a virtual secretome array. Clin Cancer Res. 2015;21(21):4960–9. doi:10.1158/1078-0432.CCR-14-3173.CrossRefPubMed Vathipadiekal V, Wang V, Wei W, Waldron L, Drapkin R, Gillette M, et al. Creation of a human secretome: a novel composite library of human secreted proteins—validation using ovarian cancer gene expression data and a virtual secretome array. Clin Cancer Res. 2015;21(21):4960–9. doi:10.​1158/​1078-0432.​CCR-14-3173.CrossRefPubMed
9.
Zurück zum Zitat Bowen NJ, Walker LD, Matyunina LV, Logani S, Totten KA, Benigno BB, et al. Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genom. 2009;2:71. doi:10.1186/1755-8794-2-71.CrossRef Bowen NJ, Walker LD, Matyunina LV, Logani S, Totten KA, Benigno BB, et al. Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells. BMC Med Genom. 2009;2:71. doi:10.​1186/​1755-8794-2-71.CrossRef
12.
Zurück zum Zitat Elgaaen BV, Olstad OK, Haug KB, Brusletto B, Sandvik L, Staff AC, et al. Global miRNA expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed miRNAs including miR-200c-3p as a prognostic marker. BMC Cancer. 2014;14:80. doi:10.1186/1471-2407-14-80.CrossRef Elgaaen BV, Olstad OK, Haug KB, Brusletto B, Sandvik L, Staff AC, et al. Global miRNA expression analysis of serous and clear cell ovarian carcinomas identifies differentially expressed miRNAs including miR-200c-3p as a prognostic marker. BMC Cancer. 2014;14:80. doi:10.​1186/​1471-2407-14-80.CrossRef
13.
Zurück zum Zitat Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 2013;41(Database issue):D991–5. doi:10.1093/nar/gks1193.CrossRefPubMed Barrett T, Wilhite SE, Ledoux P, Evangelista C, Kim IF, Tomashevsky M, et al. NCBI GEO: archive for functional genomics data sets—update. Nucleic Acids Res. 2013;41(Database issue):D991–5. doi:10.​1093/​nar/​gks1193.CrossRefPubMed
15.
Zurück zum Zitat Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–52. doi:10.1093/nar/gku1003.CrossRefPubMed Szklarczyk D, Franceschini A, Wyder S, Forslund K, Heller D, Huerta-Cepas J, et al. STRING v10: protein-protein interaction networks, integrated over the tree of life. Nucleic Acids Res. 2015;43(Database issue):D447–52. doi:10.​1093/​nar/​gku1003.CrossRefPubMed
16.
Zurück zum Zitat Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genom Res. 2003;13(11):2498–504. doi:10.1101/gr.1239303.CrossRef Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genom Res. 2003;13(11):2498–504. doi:10.​1101/​gr.​1239303.CrossRef
17.
Zurück zum Zitat Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform. 2003;4:2.CrossRef Bader GD, Hogue CW. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinform. 2003;4:2.CrossRef
19.
Zurück zum Zitat Gyorffy B, Lanczky A, Szallasi Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 2012;19(2):197–208. doi:10.1530/ERC-11-0329.CrossRefPubMed Gyorffy B, Lanczky A, Szallasi Z. Implementing an online tool for genome-wide validation of survival-associated biomarkers in ovarian-cancer using microarray data from 1287 patients. Endocr Relat Cancer. 2012;19(2):197–208. doi:10.​1530/​ERC-11-0329.CrossRefPubMed
20.
Zurück zum Zitat Wan J, Shi F, Xu Z, Zhao M. Knockdown of eIF4E suppresses cell proliferation, invasion and enhances cisplatin cytotoxicity in human ovarian cancer cells. Int J Oncol. 2015;47(6):2217–25. doi:10.3892/ijo.2015.3201.PubMed Wan J, Shi F, Xu Z, Zhao M. Knockdown of eIF4E suppresses cell proliferation, invasion and enhances cisplatin cytotoxicity in human ovarian cancer cells. Int J Oncol. 2015;47(6):2217–25. doi:10.​3892/​ijo.​2015.​3201.PubMed
23.
24.
Zurück zum Zitat Kreis NN, Friemel A, Zimmer B, Roth S, Rieger MA, Rolle U, et al. Mitotic p21Cip1/CDKN1A is regulated by cyclin-dependent kinase 1 phosphorylation. Oncotarget. 2016. doi:10.18632/oncotarget.10330. Kreis NN, Friemel A, Zimmer B, Roth S, Rieger MA, Rolle U, et al. Mitotic p21Cip1/CDKN1A is regulated by cyclin-dependent kinase 1 phosphorylation. Oncotarget. 2016. doi:10.​18632/​oncotarget.​10330.
25.
Zurück zum Zitat Tu Y, Kim E, Gao Y, Rankin GO, Li B, Chen YC. Theaflavin-3, 3′-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells. Int J Oncol. 2016;48(6):2657–65. doi:10.3892/ijo.2016.3472.PubMedPubMedCentral Tu Y, Kim E, Gao Y, Rankin GO, Li B, Chen YC. Theaflavin-3, 3′-digallate induces apoptosis and G2 cell cycle arrest through the Akt/MDM2/p53 pathway in cisplatin-resistant ovarian cancer A2780/CP70 cells. Int J Oncol. 2016;48(6):2657–65. doi:10.​3892/​ijo.​2016.​3472.PubMedPubMedCentral
26.
28.
Zurück zum Zitat Brendle A, Brandt A, Johansson R, Enquist K, Hallmans G, Hemminki K, et al. Single nucleotide polymorphisms in chromosomal instability genes and risk and clinical outcome of breast cancer: a Swedish prospective case–control study. Eur J Cancer. 2009;45(3):435–42. doi:10.1016/j.ejca.2008.10.001.CrossRefPubMed Brendle A, Brandt A, Johansson R, Enquist K, Hallmans G, Hemminki K, et al. Single nucleotide polymorphisms in chromosomal instability genes and risk and clinical outcome of breast cancer: a Swedish prospective case–control study. Eur J Cancer. 2009;45(3):435–42. doi:10.​1016/​j.​ejca.​2008.​10.​001.CrossRefPubMed
30.
Zurück zum Zitat Zhuo YJ, Xi M, Wan YP, Hua W, Liu YL, Wan S, et al. Enhanced expression of centromere protein F predicts clinical progression and prognosis in patients with prostate cancer. Int J Mol Med. 2015;35(4):966–72. doi:10.3892/ijmm.2015.2086.PubMed Zhuo YJ, Xi M, Wan YP, Hua W, Liu YL, Wan S, et al. Enhanced expression of centromere protein F predicts clinical progression and prognosis in patients with prostate cancer. Int J Mol Med. 2015;35(4):966–72. doi:10.​3892/​ijmm.​2015.​2086.PubMed
31.
Zurück zum Zitat Martens-de Kemp SR, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ, et al. Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer. Clin Cancer Res. 2013;19(8):1994–2003. doi:10.1158/1078-0432.CCR-12-2539.CrossRefPubMed Martens-de Kemp SR, Nagel R, Stigter-van Walsum M, van der Meulen IH, van Beusechem VW, Braakhuis BJ, et al. Functional genetic screens identify genes essential for tumor cell survival in head and neck and lung cancer. Clin Cancer Res. 2013;19(8):1994–2003. doi:10.​1158/​1078-0432.​CCR-12-2539.CrossRefPubMed
33.
Zurück zum Zitat Mirzaa GM, Enyedi L, Parsons G, Collins S, Medne L, Adams C, et al. Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature. Am J Med Genetics Part A. 2014;164A(11):2879–86. doi:10.1002/ajmg.a.36707.CrossRef Mirzaa GM, Enyedi L, Parsons G, Collins S, Medne L, Adams C, et al. Congenital microcephaly and chorioretinopathy due to de novo heterozygous KIF11 mutations: five novel mutations and review of the literature. Am J Med Genetics Part A. 2014;164A(11):2879–86. doi:10.​1002/​ajmg.​a.​36707.CrossRef
34.
Zurück zum Zitat Seo DW, You SY, Chung WJ, Cho DH, Kim JS, Oh JS. Zwint-1 is required for spindle assembly checkpoint function and kinetochore-microtubule attachment during oocyte meiosis. Sci Rep. 2015;5:15431. doi:10.1038/srep15431.CrossRef Seo DW, You SY, Chung WJ, Cho DH, Kim JS, Oh JS. Zwint-1 is required for spindle assembly checkpoint function and kinetochore-microtubule attachment during oocyte meiosis. Sci Rep. 2015;5:15431. doi:10.​1038/​srep15431.CrossRef
35.
Zurück zum Zitat Endo H, Ikeda K, Urano T, Horie-Inoue K, Inoue S. Terf/TRIM17 stimulates degradation of kinetochore protein ZWINT and regulates cell proliferation. J Biochem. 2012;151(2):139–44. doi:10.1093/jb/mvr128.CrossRefPubMed Endo H, Ikeda K, Urano T, Horie-Inoue K, Inoue S. Terf/TRIM17 stimulates degradation of kinetochore protein ZWINT and regulates cell proliferation. J Biochem. 2012;151(2):139–44. doi:10.​1093/​jb/​mvr128.CrossRefPubMed
37.
Zurück zum Zitat Zuberi M, Mir R, Das J, Ahmad I, Javid J, Yadav P, et al. Erratum to: Expression of serum miR-200a, miR-200b and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features. Clin Transl Oncol. 2015;17(10):840. doi:10.1007/s12094-015-1355-2.CrossRefPubMed Zuberi M, Mir R, Das J, Ahmad I, Javid J, Yadav P, et al. Erratum to: Expression of serum miR-200a, miR-200b and miR-200c as candidate biomarkers in epithelial ovarian cancer and their association with clinicopathological features. Clin Transl Oncol. 2015;17(10):840. doi:10.​1007/​s12094-015-1355-2.CrossRefPubMed
38.
Zurück zum Zitat Meng X, Muller V, Milde-Langosch K, Trillsch F, Pantel K, Schwarzenbach H. Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget. 2016;7(13):16923–35. doi:10.18632/oncotarget.7850.PubMedPubMedCentral Meng X, Muller V, Milde-Langosch K, Trillsch F, Pantel K, Schwarzenbach H. Diagnostic and prognostic relevance of circulating exosomal miR-373, miR-200a, miR-200b and miR-200c in patients with epithelial ovarian cancer. Oncotarget. 2016;7(13):16923–35. doi:10.​18632/​oncotarget.​7850.PubMedPubMedCentral
Metadaten
Titel
Identification of candidate biomarkers and analysis of prognostic values in ovarian cancer by integrated bioinformatics analysis
verfasst von
Zhanzhan Xu
Yu Zhou
Yexuan Cao
Thi Lan Anh Dinh
Jing Wan
Min Zhao
Publikationsdatum
01.11.2016
Verlag
Springer US
Erschienen in
Medical Oncology / Ausgabe 11/2016
Print ISSN: 1357-0560
Elektronische ISSN: 1559-131X
DOI
https://doi.org/10.1007/s12032-016-0840-y

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