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. 2021 Jan 14:2021:8844261.
doi: 10.1155/2021/8844261. eCollection 2021.

Functional lncRNA-miRNA-mRNA Networks in Response to Baicalein Treatment in Hepatocellular Carcinoma

Xin Zhao  1 , Dongyang Tang  2 , Xiaofei Chen  3 , Shaoqing Chen  4 , Cheng Wang  5
Affiliations

Functional lncRNA-miRNA-mRNA Networks in Response to Baicalein Treatment in Hepatocellular Carcinoma

Xin Zhao et al. Biomed Res Int. .

Abstract

Introduction: Baicalein has been shown to have antitumor activities in several cancer types. However, its acting mechanisms remain to be further investigated. This work is aimed at exploring the functional long noncoding RNA (lncRNA)/microRNA (miRNA)/messenger RNA (mRNA) triplets in response to baicalein in hepatocellular carcinoma (HCC) cell to understand the mechanisms of baicalein in HCC.

Methods: Differentially expressed lncRNAs (DELs) and miRNAs (DEMs) in HCC cell treated with baicalein were first screened using GSE95504 and GSE85511, respectively. miRNA targets for DELs were predicted and intersected with DEMs, after which the miRNA expression was validated using ENCORI and its prognostic value was assessed using Kaplan-Meier plotter. Potential miRNA targets were predicted by 3 prediction tools, after which expression level was validated at UALCAN and Human Protein Atlas. Kaplan-Meier plotter was used to evaluate the effects of these genes on overall survival and recurrence-free survival of HCC patients. Enrichment analyses for these genes were performed at DAVID.

Results: Here, we identified 14 overlapping DELs and 26 overlapping DEMs in the baicalein treatment group than those in the DMSO treatment group. Subsequently, by analyzing expression and clinical significance of miRNAs, hsa-miR-4443 was found as a highly potential miRNA target. Then, targets of hsa-miR-4443 were predicted and analyzed, and we found AKT1 was the most potential target for hsa-miR-4443. Hence, the lncRNAs-hsa-miR-4443-AKT1 axis that can respond to baicalein was established.

Conclusion: Collectively, we elucidated a role of lncRNAs-hsa-miR-4443-AKT1 pathway in response to baicalein treatment in HCC, which could help us understand the roles of baicalein in inhibiting cancer progression and may provide novel insights into the mechanisms behind HCC progression.

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Conflict of interest statement

There are no conflicts of interest from any of the authors.

Figures

Figure 1
Figure 1
Identification of differentially expressed lncRNAs (DELs) in HCC cell between DMSO and baicalin treatment. (a) Volcano plot showing DELs in HCC cell between the DMSO and 40 μM baicalein groups. (b) Volcano plot showing DELs in HCC cell between the DMSO and 80 μM baicalein groups. (c) Intersection of DELs of “DMSO vs. 40 μM baicalein” and “DMSO vs. 80 μM baicalein.” (d) Heatmap of DELs in HCC cell with DMSO, 40 μM baicalein, or 80 μM baicalein treatment. HCC: hepatocellular carcinoma.
Figure 2
Figure 2
Identification of differentially expressed miRNAs (DEMs) in HCC cell between DMSO and baicalin treatment. (a) Volcano plot showing DEMs in HCC cell between the DMSO and 40 μM baicalein groups. (b) Volcano plot showing DEMs in HCC cell between the DMSO and 80 μM baicalein groups. (c) Intersection of DEMs of “DMSO vs. 40 μM baicalein” and “DMSO vs. 80 μM baicalein.” (d) Heatmap of DEMs in HCC cell with DMSO, 40 μM baicalein, or 80 μM baicalein treatment. HCC: hepatocellular carcinoma.
Figure 3
Figure 3
Validation of clinical significance of hsa-miR-4443 and hsa-miR-675-5p in HCC. Effects of (a) hsa-miR-4443 and (b) hsa-miR-675-5p on the overall survival of HCC patients. HCC: hepatocellular carcinoma.
Figure 4
Figure 4
Exploration of hsa-miR-4443 expression in different tumor stage and grade of HCC. (a) hsa-miR-4443 expression level in normal liver tissues and stage 1-4 HCC tissues. (b) hsa-miR-4443 expression level in normal liver tissues and grade 1-4 HCC tissues. HCC: hepatocellular carcinoma.
Figure 5
Figure 5
Visualization of the lncRNA-miRNA-mRNA network response to baicalein treatment in HCC. Network is consisted of 3 lncRNAs, 1 miRNA, and 796 mRNAs. HCC: hepatocellular carcinoma.
Figure 6
Figure 6
Functional enrichment of the 796 mRNAs identified for hsa-miR-4443. (a) Circos plot showed the top 10 enriched GO terms. (b) Bubble plot showed the top 15 enriched KEGG terms.
Figure 7
Figure 7
Identification of hub genes in the protein-protein interaction network. (a) Top 10 hub genes identified in the protein-protein interaction network. (b) Intersection of genes of hub genes and genes enriched to the “pathway in cancer”.
Figure 8
Figure 8
Validation expression and clinical significance of AKT1, MAPK8, AR, and MDM2 in HCC. (a) Expression level of AKT1, MAPK8, AR, and MDM2 in HCC tissues and normal tissues. (b) Effects of AKT1, MAPK8, AR, and MDM2 on overall survival of HCC patients. (c) Effects of AKT1, MAPK8, AR, and MDM2 on recurrence-free survival of HCC patients. (d) Immunohistochemistry assay to indicate AKT1 and MAPK8 protein expression in HCC tissues and normal tissues. HCC: hepatocellular carcinoma.
Figure 9
Figure 9
Expression level of AKT1 and MAPK8 in HCC cell after DMSO or baicalein treatment. (a) AKT1 expression level in HCC cell with DMSO, 40 μM baicalein, or 80 μM baicalein treatment. (b) MAPK8 expression level in HCC cell with DMSO, 40 μM baicalein, or 80 μM baicalein treatment. HCC: hepatocellular carcinoma.
Figure 10
Figure 10
Correlation analysis between AKT1 expression and the infiltration of HCC immune cells. HCC: hepatocellular carcinoma.
Figure 11
Figure 11
Model of the lncRNA-hsa-miR-4443-AKT1 network and potential roles in HCC progression. HCC: hepatocellular carcinoma.
See this image and copyright information in PMC

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