Identification of invasion-metastasis-associated microRNAs in hepatocellular carcinoma based on bioinformatic analysis and experimental validation

Abstract

BackgroundHepatocellular carcinoma (HCC) is one of the most lethal cancer, mainly attributing to its high tendency to metastasis. Vascular invasion provides a direct path for solid tumor metastasis. Mounting evidence has demonstrated that microRNAs (miRNAs) are related to human cancer onset and progression including invasion and metastasis.MethodsIn search of invasion-metastasis-associated miRNAs in HCC, microarray dataset GSE67140 was downloaded from the Gene Expression Omnibus database. Differentially expressed miRNAs (DE-miRNAs) were obtained by R software package and the potential target genes were predicted by miRTarBase. The database for annotation, visualization and integrated discovery (DAVID) was introduced to perform functional annotation and pathway enrichment analysis for these potential targets of DE-miRNAs. Protein–protein interaction (PPI) network was established by STRING database and visualized by Cytoscape software. The effects of the miR-494-3p and miR-126-3p on migration and invasion of HCC cell lines were evaluated by conducting wound healing assay and transwell assay.ResultsA total of 138 DE-miRNAs were screened out, including 57 upregulated miRNAs and 81 downregulated miRNAs in human HCC tumors with vascular invasion compared with human HCC tumors without vascular invasion. 762 target genes of the top three upregulated and downregulated miRNAs were predicted, and they were involved in HCC-related pathways, such as pathway in cancer, focal adhesion and MAPK signaling pathway. In the PPI network, the top 10 hub nodes with higher degrees were identified as hub genes, such as TP53 and MYC. Through constructing the miRNA-hub gene network, we found that most of hub genes could be potentially modulated by miR-494-3p and miR-126-3p. Of note, miR-494-3p and miR-126-3p was markedly upregulated and downregulated in HCC cell lines and tissues, respectively. In addition, overexpression of miR-494-3p could significantly promote HCC migration and invasion whereas overexpression of miR-126-3p exerted an opposite effect.ConclusionsTargeting miR-494-3p and miR-126-3p may provide effective and promising approaches to suppress invasion and metastasis of HCC.Electronic supplementary materialThe online version of this article (10.1186/s12967-018-1639-8) contains supplementary material, which is available to authorized users.

Fidgetin as a potential prognostic biomarker for hepatocellular carcinoma

“…For early cases, hepatectomy is effective; whilst for advanced cases, systemic therapy including radiofrequency ablation, microwave ablation, percutaneous ethanol injection, transcatheter arterial chemoembolization and transplantation may not improve the poor prognosis [13]. Extensive local invasion and distant metastasis are the major reasons of deaths in patients with HCC [14,15]. Therefore, the prognostic and predictive biomarkers of tumor migrate and progression is eagerly wanted for the improvement of HCC outcomes.…”

A Key mRNA-miRNA-lncRNA Competing Endogenous RNA Triple Sub-network Linked to Diagnosis and Prognosis of Hepatocellular Carcinoma

“…Kaplan-Meier plotter database is capable to assess the effect of miRNAs and genes on survival in 21 cancer types, including hepatocellular carcinoma (21). The prognostic values of potential miRNAs in hepatocellular carcinoma was evaluated using Kaplan-Meier plotter (http://kmplot.com/analysis/) as we previously described (22,23). In brief, each miRNA of interest was first entered into this database.…”

Discovery of Potential Biomarkers Related to Aggressive Progression and Vascular Invasion of Hepatocellular Carcinoma

“…Besides, clinical characteristics among VCX3A and HCC in TCGA also showed that high expression of VCX3A was more likely to cause vascular invasion in HCC patients (Table 1). Identifying hsa-miR-664a-3p-VCX3A axis play a key role in HCC First, we predicted upstream miRNAs of VCX3A through TargetScan, miRWalk and miRDB three databases, since increasing studies have indicated that miRNAs take part in the invasion and metastasis of multiple tumors and play signi cant functions in cancer development [15][16][17]. As presented in Figure 4A-B, a total of 15 miRNAs (hsa-miR-2861, hsa-miR-5739, hsa-miR-4505, hsa-miR-6770-3p, hsa-miR-7855-5p, hsa-miR-4299, hsa-miR-6871-3p, hsa-miR-31-5p, hsa-miR-181a-5p, hsa-miR-450b-5p, hsa-miR-3615, hsa-miR-5696, hsa-miR-664b-3p, hsa-miR-579-3p, hsa-miR-664a-3p) appeared twice or more than twice in three predicting databases were selected for the further analysis.…”