Promoter Hypomethylation and miR-145-5p Downregulation- Mediated HDAC11 Overexpression Promotes Sorafenib Resistance and Metastasis of Hepatocellular Carcinoma Cells

Background Growing evidences indicate that circular RNAs (circRNAs) play an important role in the regulation of biological behavior of tumor. We aim to explore the role of circRNA in glioma and elucidate how circRNA acts. Methods Real-time PCR was used to examine the expression of circPTN in glioma tissues and normal brain tissues (NBT). Assays of dual- luciferase reporter system, biotin label RNA pull-down and FISH were used to determine that circPTN could sponge miR-145-5p and miR-330-5p. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs). Cell counting Kit-8 (CCK8), EdU assay and flow cytometry were used to investigate proliferation and cell cycle. Intracranial xenograft was established to determine how circPTN impacts in vivo. Tumor sphere formation assay was performed to determine self- renewal of glioma stem cell (GSCs). Results We demonstrated circPTN was significantly higher expression in glioma tissues and glioma cell lines, compared with NBT and HEB (human astrocyte). In gain- and loss-of-function experiments, circPTN significantly promoted glioma growth in vitro and in vivo. Furthermore, we performed dual-luciferase reporter assays and RNA pull-down assays to verify that circPTN acts through sponging miR-145-5p and miR-330-5p. Increasing expression of circPTN rescued the inhibition of proliferation and downregulation of SOX9/ITGA5 in glioma cells by miR-145-5p/miR-330-5p. In addition, we found that circPTN promoted self-renewal and increased the expression of stemness markers (Nestin, CD133, SOX9, and SOX2) via sponging miR-145-5p. Moreover, this regulation was disappeared when circPTN binding sites in miR-145-5p were mutated. Conclusions Our results suggest that circPTN is an oncogenic factor that acts by sponging miR-145-5p/miR-330-5p in glioma. Electronic supplementary material The online version of this article (10.1186/s13046-019-1376-8) contains supplementary material, which is available to authorized users.

Background Hepatitis B virus (HBV) is one of the major risk factors of hepatocellular carcinoma (HCC). Increasing evidence indicates that microRNA (miRNA)–mRNA axis is involved in HCC. However, a comprehensive miRNA–mRNA regulatory network in HBV-related HCC is still absent. This study aims to identify potential miRNA–mRNA regulatory pathways contributing to pathogenesis of HBV-related HCC. Methods Microarray GSE69580 was downloaded from Gene Expression Omnibus (GEO) database. GEO2R and ‘R-limma’ were used to conduct differential expression analysis. The common miRNAs appeared in the two analytic sets were screened as potential differentially expressed miRNAs (DE-miRNAs). The prognostic roles of screened DE-miRNAs in HCC were further evaluated using Kaplan–Meier plotter database. Target genes of DE-miRNAs were predicted by miRNet. Then, protein–protein interaction (PPI) networks were established for these targets via the STRING database, after which hub genes in the networks were identified by Cytoscape. Functional annotation and pathway enrichment analyses for the target genes were performed through DAVID database. Three enriched pathways related to HBV-related HCC were selected for further analysis and potential target genes commonly appeared in all three pathways were screened. Cytoscape was employed to construct miRNA-hub gene network. The expression and correlation of potential miRNAs and targets were further detected in clinical HBV-related HCC samples by qRT-PCR. Results 7 upregulated and 9 downregulated DE-miRNAs were accessed. 5 of 7 upregulated DE-miRNAs and 5 of 7 downregulated DE-miRNAs indicated significant prognostic roles in HCC. 2312 and 1175 target genes were predicted for the upregulated and downregulated DE-miRNAs, respectively. TP53 was identified as the hub gene in the PPI networks. Pathway enrichment analysis suggested that these predicted targets were linked to hepatitis B, pathways in cancer, microRNAs in cancer and viral carcinogenesis. Further analysis of these pathways screened 20 and 16 target genes for upregulated and downregulated DE-miRNAs, respectively. By detecting the expression of 36 target genes, six candidate target genes were identified. Finally, a potential miRNA–mRNA regulatory network was established based on the results of qRT-PCR and expression correlation analysis. Conclusions In the study, potential miRNA–mRNA regulatory pathways were identified, exploring the underlying pathogenesis and effective therapy strategy of HBV-related HCC. Electronic supplementary material The online version of this article (10.1186/s12967-018-1761-7) contains supplementary material, which is available to authorized users.

MicroRNAs (miRNAs), a class of emerging small non-coding RNAs, serve as vital players in modulating multiple biological processes via the post-transcriptional regulation of gene expression. Dysregulated expression of miRNAs in liver cancer is well documented, and the involvement of miRNAs in liver cancer initiation and progression has also been described. Cancer stem cells (CSCs) are a subset of cells known to be at the root of cancer recurrence and resistance to therapy. In this review, we highlight recent reports indicating that miRNAs participate in the regulation of liver cancer stem cells (LCSCs). The Wnt signaling pathway, TGF-beta signaling pathway, JAK/STAT signaling pathway and epithelial-mesenchymal transition (EMT) are all closely correlated with the miRNA modulation of LCSCs. In addition, several miRNAs have been demonstrated to be involved in the regulation of LCSCs in response to therapy sensitivity. Targeting LCSCs by regulating the expression of these miRNAs represents a potential therapeutic strategy for treating cancer drug resistance, metastasis and recurrence in the near future.