Screening the key microRNAs and transcription factors in prostate cancer based on microRNA functional synergistic relationships

Abstract

Prostate cancer (PC) is a common neoplasm, and metastatic PC remains incurable. The study aims to screen key microRNAs (miRNAs) and transcription factors (TFs) involved in PC.The miRNA expression profile dataset (GSE45604) was downloaded from Gene Expression Omnibus database, including 50 PC and 10 normal specimens. Differentially expressed miRNAs (DEmiRNAs) were identified through limma package in R, and DEmiRNA-DEmiRNA co-regulation network was constructed based on the number of co-regulated target genes. Functional enrichment analysis of co-regulated target genes was performed using clusterProfiler package in R, and miRNA interactions sharing at least 1 functional term were used to construct a DEmiRNA-DEmiRNA functional synergistic network (MFSN). Based on Transcriptional Regulatory Element Database, cancer-related TFs which were co-regulated by DEmiRNAs were utilized to construct a DEmiRNA-TF regulation network.A total of 66 DEmiRNAs were identified, including 7 up-regulated miRNAs with 18,642 target genes and 59 down-regulated miRNAs with 130,694 target genes. Then, the DEmiRNA-DEmiRNA co-regulation network was constructed, including 66 DEmiRNAs and 2024 co-regulation relationships. In MFSN, hsa-miR-1184, hsa-miR-1207-5p, and hsa-miR-24 had significant functional synergistic relationships. The DEmiRNA-TF network contained 6 up-regulated DEmiRNAs and 4 of them were highlighted, as hsa-miR-1184, hsa-miR-1207-5p, hsa-miR-182, and hsa-miR-183. In subnetwork of the 4 miRNAs, peroxisome proliferative activated receptor, alpha (PPARA) and cyclic AMP-responsive element modulator (CREM) were the critical regulated TFs.Four up-regulated miRNAs (hsa-miR-1207-5p, hsa-miR-1184, hsa-miR-182, and hsa-miR-183) and 2 TFs (PPARA and CREM) were identified as key regulators in PC progression. The above 4 miRNAs might participate in PC progression by targeting PPARA and CREM.

Figure 1

Flow chart of the analyses in this study. PC = prostate cancer.

Figure 2

DEmiRNA–DEmiRNA co-regulation network. Edges represent the target genes co-regulated by a pair of miRNAs. Edge thickness represents the number of co-regulated target genes. Red nodes represent up-regulated DEmiRNAs, and yellow nodes represent down-regulated DEmiRNAs.

Figure 3

DEmiRNA–DEmiRNA functional synergistic network. Edge thickness represents the number of GO BP terms enriched by co-regulated target genes. Red nodes represent up-regulated DEmiRNAs, and yellow nodes represent down-regulated DEmiRNAs. BP = biological process, GO = gene ontology.

Figure 4

Regulation networks between 52 cancer-related TFs and the corresponding DEmiRNAs. Yellow triangles represent cancer-related TFs. Red nodes represent up-regulated DEmiRNAs. Purple nodes represent down-regulated DEmiRNAs. TFs = transcription factors.

Figure 5

Regulation subnetworks between cancer-related TFs and the corresponding DEmiRNAs. Yellow triangles represent cancer-related TFs. Red nodes represent up-regulated DEmiRNAs. The 2 aggravated yellow triangles represent the TFs co-regulated by 4 DEmiRNAs. TFs = transcription factors.