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. 2019 Feb;17(2):1695-1713.
doi: 10.3892/ol.2018.9748. Epub 2018 Nov 22.

Oncogenic value of microRNA-15b-5p in hepatocellular carcinoma and a bioinformatics investigation

Wen-Ya Pan  1 , Jiang-Hui Zeng  1 , Dong-Yue Wen  2 , Jie-Yu Wang  1 , Peng-Peng Wang  3 , Gang Chen  1 , Zhen-Bo Feng  1
Affiliations

Oncogenic value of microRNA-15b-5p in hepatocellular carcinoma and a bioinformatics investigation

Wen-Ya Pan et al. Oncol Lett. 2019 Feb.

Abstract

miR-15b-5p has frequently been reported to function as a biomarker in some malignancies; however, the function of miR-15b-5p in hepatocellular carcinoma (HCC) and its molecular mechanism are still not well understood. The present study was designed to confirm the clinical value of miR-15b-5p and further explore its underlying molecular mechanism. A comprehensive investigation of the clinical value of miR-15b-5p in HCC was investigated by data mining The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets as well as literature. In addition, intersected target genes of miR-15b-5p were predicted using the miRWalk database and differentially expressed genes of HCC from TCGA. Furthermore, gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were carried out. Then, a protein-protein interaction network (PPI) was constructed to reveal the interactions between some hub target genes of miR-15b-5p. The miR-15b-5p expression level in HCC was predominantly overexpressed compared with non-HCC tissues samples (SMD=0.618, 95% CI: 0.207, 1.029; P<0.0001) based on 991 HCC and 456 adjacent non-HCC tissue samples. The pooled summary receiver operator characteristic (SROC) of miR-15b-5p was 0.81 (Q*=0.74), and the pooled sensitivity and specificity of miR-15b-5p in HCC were 72% (95% CI: 69-75%) and 68% (95% CI: 65-72%), respectively. Bioinformatically, 225 overlapping genes were selected as prospective target genes of miR-15b-5p in HCC, and profoundly enriched GO terms and KEGG pathway investigation in silico demonstrated that the target genes were associated with prostate cancer, proximal tubule bicarbonate reclamation, heart trabecula formation, extracellular space, and interleukin-1 receptor activity. Five genes (ACACB, RIPK4, MAP2K1, TLR4 and IGF1) were defined as hub genes from the PPI network. The high expression of miR-15b-5p could play an essential part in hepatocarcinogenesis through diverse regulation approaches.

Keywords: GEO; TCGA; hepatocellular carcinoma; miR-15b-5p; target genes.

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Figures

Figure 1.
Figure 1.
Framework of the present study.
Figure 2.
Figure 2.
Expression level of each study from TCGA and GEO. (A) TCGA, (B) GSE10694, (C) GSE12717, (D) GSE21362, (E) GSE22058, (F) GSE40744, (G) GSE41874, (H) GSE54751, (I) GSE57555, (J) GSE67882, (K) GSE74618 and (L) GSE69580.
Figure 3.
Figure 3.
Receiver operating characteristic (ROC) curves based on the TCGA and GEO datasets. (A) TCGA, (B) GSE10694, (C) GSE12717, (D) GSE21362, (E) GSE22058, (F) GSE40744, (G) GSE41874, (H) GSE54751, (I) GSE57555, (J) GSE67882, (K) GSE74618 and (L) GSE69580.
Figure 4.
Figure 4.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR analysis of the qualified studies of miR-15b-5p in the HCC group compared with the control group. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity; PLR, positive likelihood ratio; NLR; negative likelihood ratio; DOR, diagnostic odds ratio; HCC, hepatocellular carcinoma.
Figure 5.
Figure 5.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR of miR-15b-5p in tissues. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity; PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio.
Figure 6.
Figure 6.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR of miR-15b-5p in serum/plasma. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity, PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio.
Figure 7.
Figure 7.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR of miR-15b-5p in healthy people. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity; PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio.
Figure 8.
Figure 8.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR of miR-15b-5p in adjacent non-cancerous hepatic tissues. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity; PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio.
Figure 9.
Figure 9.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR of miR-15b-5p in HCC and HBV+ or HCV+ patients. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity; PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio; HCC, hepatocellular carcinoma.
Figure 10.
Figure 10.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR of miR-15b-5p in liver cirrhosis. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity; PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio.
Figure 11.
Figure 11.
The pooled (A) SROC curve, (B) SEN, (C) SPE, (D) PLR, (E) NLR and (F) DOR of miR-15b-5p in HBV+/HCV+ and cirrhosis. SROC, summarized receiver operating characteristic; SEN, sensitivity; SPE, specificity; PLR, positive likelihood ratio; NLR, negative likelihood ratio; DOR, diagnostic odds ratio.
Figure 12.
Figure 12.
Forest plots of studies calculating the SMD of miR-15b-5p expression in (A) the HCC group, (B) tissues, (C) healthy people, (D) adjacent non-cancerous hepatic tissues, (E) HCC and HBV+ or HCV+ patients, (F) liver cirrhosis and (G) HBV+/HCV+ and cirrhosis compared with the control group based on the random effect model. SMD, standard mean difference; HCC, hepatocellular carcinoma.
Figure 13.
Figure 13.
Symmetrical Deek's funnel plot are used to estimate the publication bias between the different subgroups. (A) HCC group, (B) tissues, (C) serum/plasma, (D) healthy people, (E) adjacent non-cancerous hepatic tissues, (F) HCC and HBV+ or HCV+ patients, (G) liver cirrhosis and (H) HBV+/HCV+ and cirrhosis.
Figure 14.
Figure 14.
KEGG and GO analysis of miR-15b-5p target genes. (A) KEGG analysis of the miR-15b-5p target genes. (B) GO functional annotation according to the putative target genes of miR-15b-5p in HCC. KEGG, Kyoto Encyclopedia of Genes and Genomes; GO, Gene ontology; HCC, hepatocellular carcinoma
Figure 15.
Figure 15.
GO functional annotation according to the putative target genes of miR-15b-5p in HCC using the BiNGO plugin in Cytoscape. GO, Gene ontology; HCC, hepatocellular carcinoma.
Figure 16.
Figure 16.
PPI network of the target genes of miR-15b-5p. A total of 224 nodes and 221 edges composed the network. The graph hides the disconnected nodes in the network and the top 5 hub genes with the most interaction lines in PPI analysis. PPI, protein-protein interactions.
Figure 17.
Figure 17.
mRNA expression levels of three hub target genes of miR-15b-5p in HCC. The mRNA expression levels of these targets were calculated by TCGA. (A, C and E) The mRNA levels were significantly downregulated in HCC tissues compared to those in non-cancerous liver tissues. (B, D and F) The relevant relationship between the expression of targets and miR-15b-5p. HCC, hepatocellular carcinoma; TCGA, The Cancer Genome Atlas.
Figure 18.
Figure 18.
mRNA expression levels of two hub target genes of miR-15b-5p in HCC. The mRNA expression levels of these targets were calculated by TCGA. (A and C) The mRNA levels were significantly downregulated in HCC tissues compared to those in non-cancerous liver tissues. (B and D) The relevant relationship between the expression of targets and miR-15b-5p. HCC, hepatocellular carcinoma; TCGA, The Cancer Genome Atlas.
Figure 19.
Figure 19.
Immunohistochemical staining of four hub target genes of miR-15b-5p in HCC. IHC of ACACB, MAP2K1, TLR4 and IGF1 in normal liver tissues and HCC tissues were provided by the HPA. ACACB expression in (A) normal and (B) HCC tissues (antibody HPA006554). MAP2K1 expression in (C) normal and (D) HCC tissues (antibody CAB003834). TLR4 expression in (E) normal and (F) HCC tissues (antibody CAB004025). IGF1 expression in (G) normal and (H) HCC tissues (antibody HPA048946). ACACB had medium staining and moderate intensity in cytoplasmic/membranous normal liver tissues. MAP2K1, TLR4 and IGF1 had low staining and weaker intensity in cytoplasmic/membranous normal liver tissues. By contrast, lower staining and weaker intensity of these hub genes was detected in HCC tissues. Immunohistochemical images were obtained using a microscope (magnification, ×40 or ×400). IHC, immunohistochemistry; HPA, Human Protein Atlas; HCC, hepatocellular carcinoma.
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