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Published in: International Journal of Hematology 1/2017

01-07-2017 | Original Article

Identification of key genes and construction of microRNA–mRNA regulatory networks in multiple myeloma by integrated multiple GEO datasets using bioinformatics analysis

Authors: Hongyu Gao, Huihan Wang, Wei Yang

Published in: International Journal of Hematology | Issue 1/2017

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Abstract

Multiple myeloma (MM) is a common hematological malignancy. To identify key genes and microRNAs in MM, we downloaded two gene expression profiles (GSE16558 and GSE47552) and two microRNA expression profiles (GSE17498 and GSE16558) from the Gene Expression Omnibus (GEO) database. A total of 596 differentially expressed genes (DEGs) and 39 differentially expressed microRNAs (DEMs) were screened out. Pathway analysis showed that upregulated genes were mainly enriched in the “B cell receptor signaling pathway”, “Cell cycle” and “NF-kappa B signaling pathway”, whereas downregulated genes were mainly enriched in the “Ribosome”, “FoxO signaling pathway” and “p53 signaling pathway”. We subsequently constructed a protein–protein interaction network of DEGs consisting of 277 genes and 563 interactions. In addition, 32 genes with high degrees in the network were identified as hub genes in MM, e.g. HDAC2, RBBP4, CREB1, and RB1. Additionally, we constructed a microRNA–mRNA regulatory network depicting interactions between DEMs and their targets, including the miR-135b–GADD45A and miR-148a–USPL1 pairs. In conclusion, the results of this data mining and integration help reveal the molecular basis of MM pathogenesis as well as potential biomarkers and therapeutic targets for MM diagnosis and treatment.
Literature
2.
go back to reference Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH, et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood. 2009;114(4):791–5. doi:10.1182/blood-2008-12-191676.CrossRefPubMedPubMedCentral Landgren O, Kristinsson SY, Goldin LR, Caporaso NE, Blimark C, Mellqvist UH, et al. Risk of plasma cell and lymphoproliferative disorders among 14621 first-degree relatives of 4458 patients with monoclonal gammopathy of undetermined significance in Sweden. Blood. 2009;114(4):791–5. doi:10.​1182/​blood-2008-12-191676.CrossRefPubMedPubMedCentral
6.
go back to reference Rio-Machin A, Ferreira BI, Henry T, Gomez-Lopez G, Agirre X, Alvarez S, et al. Downregulation of specific miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect of IgH translocations occurring in the non-hyperdiploid subtype. Leukemia. 2013;27(4):925–31. doi:10.1038/leu.2012.302.CrossRefPubMed Rio-Machin A, Ferreira BI, Henry T, Gomez-Lopez G, Agirre X, Alvarez S, et al. Downregulation of specific miRNAs in hyperdiploid multiple myeloma mimics the oncogenic effect of IgH translocations occurring in the non-hyperdiploid subtype. Leukemia. 2013;27(4):925–31. doi:10.​1038/​leu.​2012.​302.CrossRefPubMed
7.
go back to reference Lionetti M, Biasiolo M, Agnelli L, Todoerti K, Mosca L, Fabris S, et al. Identification of microRNA expression patterns and definition of a microRNA/mRNA regulatory network in distinct molecular groups of multiple myeloma. Blood. 2009;114(25):e20–6. doi:10.1182/blood-2009-08-237495.CrossRefPubMed Lionetti M, Biasiolo M, Agnelli L, Todoerti K, Mosca L, Fabris S, et al. Identification of microRNA expression patterns and definition of a microRNA/mRNA regulatory network in distinct molecular groups of multiple myeloma. Blood. 2009;114(25):e20–6. doi:10.​1182/​blood-2009-08-237495.CrossRefPubMed
8.
go back to reference Sharma A, Heuck CJ, Fazzari MJ, Mehta J, Singhal S, Greally JM, et al. DNA methylation alterations in multiple myeloma as a model for epigenetic changes in cancer. Wiley Interdiscip Rev Syst Biol Med. 2010;2(6):654–69. doi:10.1002/wsbm.89.CrossRefPubMed Sharma A, Heuck CJ, Fazzari MJ, Mehta J, Singhal S, Greally JM, et al. DNA methylation alterations in multiple myeloma as a model for epigenetic changes in cancer. Wiley Interdiscip Rev Syst Biol Med. 2010;2(6):654–69. doi:10.​1002/​wsbm.​89.CrossRefPubMed
14.
17.
go back to reference Zhao J, Xie C, Edwards H, Wang G, Taub JW, Ge Y. Histone deacetylases 1 and 2 cooperate in regulating BRCA1, CHK1, and RAD51 expression in acute myeloid leukemia cells. Oncotarget. 2016;. doi:10.18632/oncotarget.14062. Zhao J, Xie C, Edwards H, Wang G, Taub JW, Ge Y. Histone deacetylases 1 and 2 cooperate in regulating BRCA1, CHK1, and RAD51 expression in acute myeloid leukemia cells. Oncotarget. 2016;. doi:10.​18632/​oncotarget.​14062.
21.
go back to reference Zhang W, Tyl M, Ward R, Sobott F, Maman J, Murthy AS, et al. Structural plasticity of histones H3–H4 facilitates their allosteric exchange between RbAp48 and ASF1. Nat Struct Mol Biol. 2013;20(1):29–35. doi:10.1038/nsmb.2446.CrossRefPubMed Zhang W, Tyl M, Ward R, Sobott F, Maman J, Murthy AS, et al. Structural plasticity of histones H3–H4 facilitates their allosteric exchange between RbAp48 and ASF1. Nat Struct Mol Biol. 2013;20(1):29–35. doi:10.​1038/​nsmb.​2446.CrossRefPubMed
22.
go back to reference Li Y, Xu D, Bao C, Zhang Y, Chen D, Zhao F, et al. MicroRNA-135b, a HSF1 target, promotes tumor invasion and metastasis by regulating RECK and EVI5 in hepatocellular carcinoma. Oncotarget. 2015;6(4):2421–33. doi:10.18632/oncotarget.2965.CrossRefPubMed Li Y, Xu D, Bao C, Zhang Y, Chen D, Zhao F, et al. MicroRNA-135b, a HSF1 target, promotes tumor invasion and metastasis by regulating RECK and EVI5 in hepatocellular carcinoma. Oncotarget. 2015;6(4):2421–33. doi:10.​18632/​oncotarget.​2965.CrossRefPubMed
23.
go back to reference He Y, Wang J, Wang J, Yung VY, Hsu E, Li A, et al. MicroRNA-135b regulates apoptosis and chemoresistance in colorectal cancer by targeting large tumor suppressor kinase 2. Am J Cancer Res. 2015;5(4):1382–95.PubMedPubMedCentral He Y, Wang J, Wang J, Yung VY, Hsu E, Li A, et al. MicroRNA-135b regulates apoptosis and chemoresistance in colorectal cancer by targeting large tumor suppressor kinase 2. Am J Cancer Res. 2015;5(4):1382–95.PubMedPubMedCentral
24.
go back to reference Wu W, Wang Z, Yang P, Yang J, Liang J, Chen Y, et al. MicroRNA-135b regulates metastasis suppressor 1 expression and promotes migration and invasion in colorectal cancer. Mol Cell Biochem. 2014;388(1–2):249–59. doi:10.1007/s11010-013-1916-z.CrossRefPubMed Wu W, Wang Z, Yang P, Yang J, Liang J, Chen Y, et al. MicroRNA-135b regulates metastasis suppressor 1 expression and promotes migration and invasion in colorectal cancer. Mol Cell Biochem. 2014;388(1–2):249–59. doi:10.​1007/​s11010-013-1916-z.CrossRefPubMed
25.
go back to reference Hua K, Jin J, Zhao J, Song J, Song H, Li D, et al. miR-135b, upregulated in breast cancer, promotes cell growth and disrupts the cell cycle by regulating LATS2. Int J Oncol. 2016;48(5):1997–2006. doi:10.3892/ijo.2016.3405.PubMed Hua K, Jin J, Zhao J, Song J, Song H, Li D, et al. miR-135b, upregulated in breast cancer, promotes cell growth and disrupts the cell cycle by regulating LATS2. Int J Oncol. 2016;48(5):1997–2006. doi:10.​3892/​ijo.​2016.​3405.PubMed
27.
go back to reference Liebermann DA, Tront JS, Sha X, Mukherjee K, Mohamed-Hadley A, Hoffman B. Gadd45 stress sensors in malignancy and leukemia. Crit Rev Oncogenesis. 2011;16(1–2):129–40.CrossRefPubMedPubMedCentral Liebermann DA, Tront JS, Sha X, Mukherjee K, Mohamed-Hadley A, Hoffman B. Gadd45 stress sensors in malignancy and leukemia. Crit Rev Oncogenesis. 2011;16(1–2):129–40.CrossRefPubMedPubMedCentral
28.
go back to reference Guo W, Dong Z, Guo Y, Chen Z, Kuang G, Yang Z. Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma. Int J Cancer. 2013;133(9):2043–53. doi:10.1002/ijc.28223.CrossRefPubMed Guo W, Dong Z, Guo Y, Chen Z, Kuang G, Yang Z. Methylation-mediated repression of GADD45A and GADD45G expression in gastric cardia adenocarcinoma. Int J Cancer. 2013;133(9):2043–53. doi:10.​1002/​ijc.​28223.CrossRefPubMed
29.
33.
go back to reference Porstner M, Winkelmann R, Daum P, Schmid J, Pracht K, Corte-Real J, et al. miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2. Eur J Immunol. 2015;45(4):1206–15. doi:10.1002/eji.201444637.CrossRefPubMed Porstner M, Winkelmann R, Daum P, Schmid J, Pracht K, Corte-Real J, et al. miR-148a promotes plasma cell differentiation and targets the germinal center transcription factors Mitf and Bach2. Eur J Immunol. 2015;45(4):1206–15. doi:10.​1002/​eji.​201444637.CrossRefPubMed
37.
44.
go back to reference Bermejo JL, Kabisch M, Dunnebier T, Schnaidt S, Melchior F, Fischer HP, et al. Exploring the association between genetic variation in the SUMO isopeptidase gene USPL1 and breast cancer through integration of data from the population-based GENICA study and external genetic databases. Int J Cancer. 2013;133(2):362–72. doi:10.1002/ijc.28040.CrossRefPubMed Bermejo JL, Kabisch M, Dunnebier T, Schnaidt S, Melchior F, Fischer HP, et al. Exploring the association between genetic variation in the SUMO isopeptidase gene USPL1 and breast cancer through integration of data from the population-based GENICA study and external genetic databases. Int J Cancer. 2013;133(2):362–72. doi:10.​1002/​ijc.​28040.CrossRefPubMed
Metadata
Title
Identification of key genes and construction of microRNA–mRNA regulatory networks in multiple myeloma by integrated multiple GEO datasets using bioinformatics analysis
Authors
Hongyu Gao
Huihan Wang
Wei Yang
Publication date
01-07-2017
Publisher
Springer Japan
Published in
International Journal of Hematology / Issue 1/2017
Print ISSN: 0925-5710
Electronic ISSN: 1865-3774
DOI
https://doi.org/10.1007/s12185-017-2216-2

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