Abstract:Objective To identify potential genetic markers associated with breast cancer metastasis and to perform survival analysis.Methods The comprehensive Gene Expression Omnibus (GEO) was used to screen differentially expressed genes (DEGs) between metastatic and non-metastatic sites of breast cancer.Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analyses were performed, the protein-protein interaction(PPI) network was constructed, and module analysis was performed using MCODE.Then, overall survival (OS) and distant metastasis free survival (DMFS) analysis of hub genes was performed by the Kaplan-Meier plotter online tool.The correlations between hub genes and clinical stages were validated through GEPIA online tool.Results A total of 295 DEGs were obtained, which were significantly enriched in the terms related to extracellular exosome, focal adhesion,cell division.KEGG pathway analysis showed that the significant pathways included mitogen-activated protein kinase(MAPK) signaling pathway, Rap1 signaling pathway, cell adhesion molecules (CAMs), antigen processing and presentation.The PPI network was established with 280 nodes and 357 edges.Ten modules were found from the PPI network.Conclusion A total of 20 genes were selected as hub genes, among which, low expression of TYMS, SKA1, ADCY7 and high expression of MX1 were related with worse overall survival.Low expression of POLR3H and high expression of CDCA8, ASE1, KIF14, MX1 were associated with worse DMFS.POLR3H and PRC1 may serve as new biomarker in diagnosing metastasis of breast cancer or potential drug target.
Siegel RL,Miller KD,Jemal A.Cancer statistics,2019[J].CA Cancer J Clin,2019,69(1):7-34.
[2]
Weigelt B,Peterse JL,Van′t Veer LJ.Breast cancer metastasis:Markers and models[J].Nat Rev Cancer,2005,5(8):591-602.
[3]
Scully OJ,Bay BH,Yip G,et al.Breast cancer metastasis[J].Cancer Genomics Proteomics,2012,9(5):311-320.
[5]
Cai Y,Mei J,Xiao Z,et al.Identification of five hub genes as monitoring biomarkers for breast cancer metastasis in silico[J].Hereditas,2019,156:20.
[10]
Ashburner M,Ball CA,Blake JA,et al.Gene ontology:Tool for the unification of biology[J].Nat Genet,2000,25(1):25-29.
[4]
Chen X,Pei Z,Peng H,et al.Exploring the molecular mechanism associated with breast cancer bone metastasis using bioinformatic analysis and microarray genetic interaction network[J].Med (United States),2018,97(37):1-7.
[6]
Zheng T,Wang A,Hu D,et al.Molecular mechanisms of breast cancer metastasis by gene expression profile analysis[J].Mol Med Rep,2017,16(4):4671-4677.
[7]
Edgar R,Domrachev M,Lash AE.Gene Expression Omnibus:NCBI gene expression and hybridization array data repository[J].Nucleic Acids Res,2002,30(1):207-210.
[8]
Xia J,Gill EE,Hancock REW.NetworkAnalyst for statistical,visual and network -based meta -analysis of gene expression data[J].Nat Protoc,2015,10(6):823-844.
[9]
Zhou G,Soufan O,Ewald J,et al.NetworkAnalyst 3.0:A visual analytics platform for comprehensive gene expression profiling and meta-analysis[J].Nucleic Acids Res,2019,47(W1):W234-W241.
[11]
Altermann E,Klaenhammer TR.PathwayVoyager:Pathway mapping using the Kyoto Encyclopedia of Genes and Genomes(KEGG) database[J].BMC Genomics,2005,6:60.
[12]
Huang DW,Sherman BT,Lempicki RA.Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources[J].Nat Protoc,2009,4(1):44-57.
[13]
Szklarczyk D,Franceschini A,Wyder S,et al.STRING v10:Protein-protein interaction networks,integrated over the tree of life[J].Nucleic Acids Res,2015,43(D1):D447-D452.
[14]
Shannon P,Markiel A,Ozier O,et al.Cytoscape:A software Environment for integrated models of biomolecular interaction networks[J].Genome Res,2003,13(11):2498-2504.
[15]
Bader GD,Hogue CWV.An automated method for finding molecular complexes in large protein interaction networks[J].BMC Bioinformatics,2003,4:2.
[16]
Gyorffy B,Lanczky A,Eklund AC,et al.An online survival analysis tool to rapidly assess the effect of 22 277 genes on breast cancer prognosis using microarray data of 1809 patients[J].Breast Cancer Res Treat,2010,123(3):725-731.
[17]
Tang Z,Li C,Kang B,et al.GEPIA:A web server for cancer and normal gene expression profiling and interactive analyses[J].Nucleic Acids Res,2017,45(W1):W98-W102.
[18]
Che YL,Luo SJ,Li G,et al.The C3G/Rap1 pathway promotes secretion of MMP-2 and MMP-9 and is involved in serous ovarian cancer metastasis[J].Cancer Lett,2015,359(2):241-249.
[19]
Peng B,He R,Xu Q,et al.Ginsenoside 20(S)-protopanaxadiol inhibits triple-negative breast cancer metastasis in vivo by targeting EGFR-mediated MAPK pathway[J].Pharmacol Res,2019,142(151):1-13.
[20]
Shao GL,Wang MC,Fan XL,et al.Correlation between Raf/MEK/ERKs signaling pathway and clinicopathological features and prognosis for patients with breast cancer having axillary lymph node metastasis[J].Technol Cancer Res Treat,2018,17(253):1-10.
[21]
Yao Y,Fang ZP,Chen H,et al.HGFK1 inhibits bone metastasis in breast cancer through the TAK1/p38 MAPK signaling pathway[J].Cancer Gene Ther,2012,19(9):601-608.
[22]
Lai YCC,Chang SJ,Kostoro J,et al.Vascular adhesion protein-1 as indicator of breast cancer tumor aggressiveness and invasiveness[J].Apmis,2018,126(9):755-761.
[23]
Shan F,Liu YL,Wang Q,et al.Thymidylate synthase predicts poor response to pemetrexed chemotherapy in patients with advanced breast cancer[J].Oncol Lett,2018,16(3):3274-3280.
[24]
Le K,Guo H,Zhang Q,et al.Gene and lncRNA co-expression network analysis reveals novel ceRNA network for triple-negative breast cancer[J].Sci Rep,2019,9(1):1-10.
[25]
Guenter J,Abadi S,Lim H,et al.Evaluating genomic biomarkers associated with resistance or sensitivity to chemotherapy in patients with advanced breast and colorectal cancer[J].J Oncol Pharm Pract,2020,27(6):1371-1381.
[26]
Fu Y,Zhou QZ,Zhang XL,et al.Identification of hub genes using co-expression network analysis in breast cancer as a tool to predict different stages[J].Med Sci Monit,2019,25:8873-8890.
[27]
Ahmed SM,Thériault BL,Uppalapati M,et al.KIF14 negatively regulates Rap 1 a-Radil signaling during breast cancer progression[J].J Cell Biol,2012,199(6):951-967.
[28]
Greenwood C,Metodieva G,Al -Janabi K,et al.Stat1 and CD74 overexpression is co -dependent and linked to increased invasion and lymph node metastasis in triple-negative breast cancer[J].J Proteomics,2012,75 (10):3031-3040.
[29]
Aljohani AI,Joseph C,Kurozumi S,et al.Myxovirus resistance 1 (MX1) is an independent predictor of poor outcome in invasive breast cancer[J].Breast Cancer Res Treat,2020,181(3):541-551.
[30]
Zhan P,Zhang B,Xi G min,et al.PRC1 contributes to tumorigenesis of lung adenocarcinoma in association with the Wnt/β-catenin signaling pathway[J].Mol Cancer,2017,16(1):1-15.
[31]
Chen J,Rajasekaran M,Xia H,et al.The microtubule-associated protein PRC1 promotes early recurrence of hepatocellular carcinoma in association with the Wnt/β-catenin signalling pathway[J].Gut,2016,65(9):1522-1534.
[32]
Yi L,Ouyang L,Wang S,et al.Long noncoding RNA PTPRG-AS1 acts as a microRNA-194-3p sponge to regulate radiosensitivity and metastasis of nasopharyngeal carcinoma cells via PRC1[J].J Cell Physiol,2019,234(10):19 088-19 102.
[33]
Brynychova V,Ehrlichova M,Hlavac V,et al.Genetic and functional analyses do not explain the association of high PRC1 expression with poor survival of breast carcinoma patients[J].Biomed Pharmacother,2016,83:857-864.
[34]
Mehra R,Vats P,Kalyana-Sundaram S,et al.Primary urethral clear -cell adenocarcinoma:Comprehensive analysis by surgical pathology,cytopathology,and next -generation sequencing[J].Am J Pathol,2014,184(3):584-591.
[35]
Yán ez Y,Grau E,Rodríguez-Cortez VC,et al.Two independent epigenetic biomarkers predict survival in neuroblastoma[J].Clin Epigenetics,2015,7(1):1-14.