LINC00606 promotes glioblastoma progression through sponge miR-486-3p and interaction with ATP11B.

BACKGROUND: LncRNAs regulate tumorigenesis and development in a variety of cancers. We substantiate for the first time that LINC00606 is considerably expressed in glioblastoma (GBM) patient specimens and is linked with adverse prognosis. This suggests that LINC00606 may have the potential to regulate glioma genesis and progression, and that the biological functions and molecular mechanisms of LINC00606 in GBM remain largely unknown. METHODS: The expression of LINC00606 and ATP11B in glioma and normal brain tissues was evaluated by qPCR, and the biological functions of the LINC00606/miR-486-3p/TCF12/ATP11B axis in GBM were verified through a series of in vitro and in vivo experiments. The molecular mechanism of LINC00606 was elucidated by immunoblotting, FISH, RNA pulldown, CHIP-qPCR, and a dual-luciferase reporter assay. RESULTS: We demonstrated that LINC00606 promotes glioma cell proliferation, clonal expansion and migration, while reducing apoptosis levels. Mechanistically, on the one hand, LINC00606 can sponge miR-486-3p; the target gene TCF12 of miR-486-3p affects the transcriptional initiation of LINC00606, PTEN and KLLN. On the other hand, it can also regulate the PI3K/AKT signaling pathway to mediate glioma cell proliferation, migration and apoptosis by binding to ATP11B protein. CONCLUSIONS: Overall, the LINC00606/miR-486-3p/TCF12/ATP11B axis is involved in the regulation of GBM progression and plays a role in tumor regulation at transcriptional and post-transcriptional levels primarily through LINC00606 sponging miR-486-3p and targeted binding to ATP11B. Therefore, our research on the regulatory network LINC00606 could be a novel therapeutic strategy for the treatment of GBM.

Identification of key genes in hepatocellular carcinoma associated with exposure to TCDD and α-endosulfan by WGCNA.

2,3,7,8-tet-rachlorodibenzo-p-dioxin (TCDD) and α-endosulfan are two typical persistent organic pollutants (POPs), both of which accumulate in the liver and have potential carcinogenic hepatic effects. The underlying molecular mechanisms of pathogenesis of hepatocellular carcinoma (HCC) remain elusive when exposure to POPs. The aim of this study is to explore the key genes involved in HCC when exposure to TCDD and α-endosulfan by weighted gene co-expression network analysis (WGCNA). First, we performed co-expressed analysis on HCC and normal condition, based on WGCNA. In results, seven co-expressed modules were identified from 56 human liver samples, and the brown module correlated with five stages of HCC. Subsequently, we predicted that human five liver diseases were associated with exposure to TCDD and/or α-endosulfan by Nextbio analysis. Functional enrichment analysis showed that the brown module enriched in oxidation-reduction process, DNA replication, oxidoreductase activity and aging, which were the same as the results when exposure to the mixture of TCDD and α-endosulfan. Lastly, based on the protein-protein interaction network, we identified three novel genes including HK2, EXO1 and PFKP as key genes in HCC associated with exposure to TCDD and α-endosulfan mixture. In addition, survival analysis of key genes in Kaplan-Meier plotter demonstrated that aberrant expression levels of all the three key genes were associated with poor prognosis of HCC. Finally, Western blot analysis confirmed that protein expression levels of PFKP and HK2 in the three exposed groups were significantly elevated, while EXO1 were significantly upregulated when exposure to TCDD and α-endosulfan mixture in HepaRG cells. This study provides a new perspective to the understanding of the genetic mechanism of HCC when exposure to POPs.

The effects of endosulfan on cell migration and invasion in prostate cancer cells via the KCNQ1OT1/miR-137-3p/PTP4A3 axis.

Endosulfan belongs to persistent organic pollutants (POPs), closely related to an increased risk of prostate cancer (PCa). The existing evidence shows that lncRNAs compete with miRNAs for binding sites and contribute to the onset and progression of human malignancies. In this study we investigate how endosulfan promotes cell migration and invasion in DU145 and PC3 prostate cancer cells through epigenetic mechanism of lncRNA-miRNA regulation. Based on our past research we focused on PTP4A3 and constructed wild-type (WT) and mutant PTP4A3 plasmids for further analysis. Our results revealed that transfection of PTP4A3-WT can lead to changes in the expression of epithelial-mesenchymal transition (EMT) biomarkers and critical proteins in the TGF-ß signaling pathway, and promote cell migration and invasion in PCa cells. Bioinformatics analysis shows that there were complementary sequences in PTP4A3 3'-UTR and KCNQ1OT1 3'-UTR to the seed sequence of hsa-miR-137-3p, and dual luciferase reporter assay indicates the potential binding capacity of miR-137-3p to 3'-UTR of PTP4A3 and KCNQ1OT1. We found that miR-137-3p mimic inhibited cell migration and invasion, as well as repressed alterations of EMT biomarkers and critical proteins in the TGF-ß signaling pathway. Rescue experiment results revealed that co-transfection of miR-137-3p mimic and PTP4A3-WT plasmid reversed these changes following transfection with miR-137-3p mimic alone. We found that KCNQ1OT1 was predominantly distributed in the cytoplasm from a subcellular fractionation assay. Functionally, silencing of KCNQ1OT1 repressed cell migration and invasion, and caused alterations of EMT biomarkers and critical proteins in the TGF-ß signaling pathway, which were all restored by co-transfection with anti-miR-137-3p or PTP4A3-WT plasmid. Furthermore, overexpression of miR-137-3p or silencing of KCNQ1OT1 dramatically rescued the effects of endosulfan on promoting cell migration and invasion. These findings suggest that endosulfan can indeed promote cell migration and invasion via the KCNQ1OT1/miR-137-3p/PTP4A3 axis in PCa cells.