Functional annotation and pathway enrichment analyses of DEGs

The biological function of the identified DEGs was determined using the following tools: ToppGene (https://toppgene.cchmc.org/) (17), which is a one-stop portal for functional enrichment analysis of gene lists based on the Gene Ontology (GO) database (18); the BioSystems database (19); the BIOCYC database (http://BioCyc.org/) (20); the Kyoto Encyclopedia of Genes and Genomes (KEGG) database (21); the REACTOME pathway database (22,23); WikiPathways September 2015 release (http://www.wikipathways.org/index.php/Wiki Pathways), GenMAPP version 2.1 (Gladstone Institutes, San Francisco, CA, USA), the MSigDB C2 database version 5.0 (http://software.broadinstitute.org/gsea/msigdb), which integrated BioCarta, (Sigma-Aldrich and Signaling Gateway; http://www.biocarta.com/), the PANTHER database version 1.4 (http://pantherdb.org/downloads/index.jsp) (24), Pathway Ontology (http://www.obofoundry.org/ontology/pw.html) (25) and the Small Molecule Pathway Database (SMPDB) version 2.0 (http://www.smpdb.ca) (26,27). FDR values of <0.05 and a gene count of ≥2 were set as the threshold values. GO categories were classified into the following terms: Biological process, molecular function and cellular component.