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. 2019 Aug 29:12:7025-7038.
doi: 10.2147/OTT.S220923. eCollection 2019.

Upregulation of long non-coding RNA FOXP4-AS1 and its regulatory network in hepatocellular carcinoma

Duo Wang #  1 , Tao Bai #  2 , Guanyu Chen  3 , Junjie Liu  1 , Miao Chen  1 , Yuan Zhao  2 , Tao Luo  2 , Jie Chen  2 , Lequn Li  2 , Chunyan Zhang  4 , Hang Li  1
Affiliations

Upregulation of long non-coding RNA FOXP4-AS1 and its regulatory network in hepatocellular carcinoma

Duo Wang et al. Onco Targets Ther. .

Abstract

Objective: FOXP4-AS1 (FOXP4 antisense RNA 1) is putatively a functional oncogene in colorectal cancer. This study constructed a regulatory network involving FOXP4-AS1 for better understanding of its function in hepatocellular carcinoma (HCC).

Methods: FOXP4-AS1 was assessed in HCC and adjacent normal (control) liver samples via quantitative real-time PCR. Differentially expressed micro RNAs (DEmiRNAs) were predicted. Their target genes were verified via the gene expression profiling interaction analysis (GEPIA) database, and subjected to gene ontology (GO) annotation and KEGG (Kyoto Encyclopedia of Genes and Genome) pathway enrichment analysis. Protein-protein interaction (PPI) networks were established and hub genes identified with Cytoscape software. The GEPIA database was used to assess the prognostic roles of 20 hub genes in liver cancer. The cBioPortal database was used to exhibit alterations of the genes.

Results: The HCC samples had significantly higher levels of FOXP4-AS1 compared with the control (P=0.001). Six upregulated and 4 downregulated DEmiRNAs were identified. Over- and under-expressed predicted target genes (183 and 147, respectively) were selected for GO annotation and KEGG pathway enrichment analysis. The downregulated genes were significantly prominent in the PI3K-Akt signaling pathway; the upregulated genes in the cell cycle. The PPI networks indicated IGFBP3 and PRC1 as hub genes with the highest node degrees. Higher expressions of 9 (6) genes were associated with worse (better) prognosis in HCC.

Conclusion: An HCC-associated FOXP4-AS1-miRNA-mRNA regulatory network was constructed, and molecular mechanisms involved in HCC development were elucidated. This work provides direction for finding new HCC therapeutic targets.

Keywords: FOXP4-AS1; hepatocellular carcinoma; long non-coding RNA; quantitative real-time PCR.

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Conflict of interest statement

The authors declare that they have no conflicts of interest in this work.

Figures

Figure 1
Figure 1
Levels of FOXP4-AS1 in HCC and control groups, based on quantitative real-time PCR data.
Figure 2
Figure 2
Kaplan-Meier curves for FOXP4-AS1 in HCC based on qRT-PCR. (A) Disease-free survivals of groups with low and high levels of FOXP4-AS1. (B) Overall survival of groups with low and high levels of FOXP4-AS1.
Figure 3
Figure 3
Venn diagram of DEmiRNAs of FOXP4-AS1.
Figure 4
Figure 4
Venn diagram of target genes of FOXP4-AS1. (A) Upregulated target genes; (B) downregulated target genes.
Figure 5
Figure 5
MiRNA-mRNA regulatory network of 6 upregulated miRNAs associated with FOXP4-AS1.
Figure 6
Figure 6
MiRNA-mRNA regulatory network of 4 downregulated miRNAs associated with FOXP4-AS1.
Figure 7
Figure 7
GO functional annotation and KEGG pathway analysis. Most prominent BP, CC, MF, and KEGG pathways associated with (A–D) upregulated and (E–H) downregulated candidate genes of FOXP4-AS1. (A, E) BP; (B, F) CC; (C, G) MF; and (D, H) KEGG pathways.
Figure 8
Figure 8
PPI network of upregulated target genes of FOXP4-AS1 in HCC.
Figure 9
Figure 9
PPI network of downregulated target genes of FOXP4-AS1 in HCC.
Figure 10
Figure 10
Expressions of 10 upregulated hub genes in HCC and normal tissues, based on GEPIA. (A) HJURP. (B) DTL. (C) CKAP2. (D) KNSTRN. (E) MCM4. (F) PRC1. (G) RPL36A. (H) SNRPD1. (I) CDCA5. (J) CENPN.
Figure 11
Figure 11
Expressions of 10 downregulated hub genes in HCC and normal tissues, based on GEPIA. (A) GHR. (B) FOSB. (C) ADRA2B. (D) ADRA1A. (E) SLC11A1. (F) NTF3. (G) NGFR. (H) IGFBP3. (I) CDF2. (J) GABBR1.
Figure 12
Figure 12
Association of expressions of 10 upregulated hub genes and the survival of patients with HCC. (A) CKAP2. (B) CENPN. (C) CDCA5. (D) SNRPD1. (E) RPL36A. (F) PRC1. (G) MCM4. (H) KNSTRN. (I) HJURP. (J) DTL.
Figure 13
Figure 13
Association of expressions of 10 downregulated hub genes and survival of patients with HCC. (A) ADRA1A. (B) SLC11A1. (C) NTF3. (D) NGFR. (E) IGFBP3. (F) GHR. (G) GDF2. (H) GABBR1. (I) FOSB. (J) ADRA2B.
Figure 14
Figure 14
Network review of genes neighboring hub genes and genetic alteration of hub genes in HCC. (A) Ten upregulated hub genes. (B) Ten downregulated hub gene. (C) Genetic alteration of 10 upregulated hub genes. (D) Genetic alteration of 10 downregulated hub genes. Association between hub genes and drugs.
Figure 15
Figure 15
Enrichment analysis of the genes altered in the 20 hub neighboring genes in HCC. Most prominent BP, CC, MF, and KEGG pathways associated with (A–D) upregulated and (E–H) downregulated hub neighboring genes of FOXP4-AS1. (A, E) BP; (B, F) CC; (C, G) MF; and (D, H) KEGG pathways.
Figure 16
Figure 16
The candidate miRNA-hub gene regulatory network in HCC.
See this image and copyright information in PMC

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