Biological function of plasmacytoma variant translocation 1 (PVT1) in influencing the progression of non-small cell lung cancer (NSCLC) through Micro ribonucleic acid (miRNA)-526b/EZH2 regulatory loop was elucidated. Relative levels of PVT1 and miRNA-526b in NSCLC tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Prognostic potential of PVT1 in NSCLC was assessed by Kaplan-Meier curves. The interaction among PVT1/miRNA-526b/EZH2 regulatory loop was confirmed by dual-luciferase reporter gene assay. Regulatory effects of PVT1/miRNA-526b/EZH2 axis on viability and wound closure of A549 cells were evaluated by cell counting kit-8 (CCK-8) and wound closure assay, respectively. PVT1 was upregulated in NSCLC tissues, while miRNA-526b was downregulated. PVT1 level was negatively related to that of miR-526 in NSCLC tissues. Worse survival was seen in NSCLC patients expressing high level of PVT1 compared to those with low level. Knockdown of PVT1 attenuated viability and wound closure ability in A549 cells, which were partially reversed after miRNA-526b knockdown. miRNA-526b is the downstream target of PVT1 and its level was negatively regulated by PVT1. EZH2 is the target gene of miRNA-526b. Transfection of miRNA-526b mimic remarkably downregulated EZH2 in A549 cells. Importantly, the attenuated viability and wound closure ability in A549 cells overexpressing miRNA-526b were reversed after EZH2 overexpression. PVT1 is upregulated in NSCLC, and predicts a poor prognosis. PVT1 accelerates the progression of NSCLC via targeting miRNA-526b/EZH2 regulatory loop.
Many reports have indicated that long non-coding RNAs (lncRNAs) are closely associated with the occurrence and development of various cancers. Musculin antisense RNA 1 (MSC-AS1) is a an lncRNA known to act as an oncogene in several types of human cancers; however, its specific function in lung adenocarcinoma (LUAD) is still unclear. For this study, we designed and conducted experiments to clarify the function of the lncRNA MSC-AS1 in LUAD and its underlying mechanisms. We found that the expression of MSC-AS1 was significantly higher in LUAD tissues and cells than that in normal ones. Through loss-of function assays, we confirmed that the proliferation of LUAD cells was significantly restrained by down-regulation of MSC-AS1 and the rate of cell apoptosis was accelerated. The results from our mechanistic experiments showed that MSC-AS1 interacts with microRNA-33b-5p (miR-33b-5p). Moreover, glycerol-3-phosphate acyltransferase, mitochondrial (GPAM) was found to be a direct target gene of miR-33b-5p, and it has similar functions to MSC-AS1. Further, inhibition of miR-33b-5p or overexpression GPAM reversed the inhibitory effects of MSC-AS1 silencing on LUAD cell growth. In short, MSC-AS1 facilitates LUAD progression through sponging miR-33b-5p to up-regulate GPAM.
Glioblastoma multiforme (GBM) is the most common type of malignant brain tumor. GBM is currently treated with temozolomide (TMZ), although patients often exhibit resistance to this agent. Although several mechanisms underlying the resistance of GBM to TMZ have been identified, the combination of these mechanisms is not sufficient to fully account for this phenomenon. Our previous study demonstrated that knocking down the Forkhead box protein O3a (FoxO3a) gene, a member of the FoxO subfamily of transcription factors, resulted in glioma cell sensitization to TMZ, accompanied by reduced levels of nuclear β-catenin. The aim of the present study was to specify how FoxO3a and β-catenin are implicated in glioma cell TMZ resistance. Using the U87 and U251 parental cell lines (also designated as sensitive cell lines) and corresponding resistant cell lines (U87-TR and U251-TR, generated by repeated TMZ treatments), coupled with a combined knockdown/overexpression strategy, it was revealed that FoxO3a or β-catenin overexpression in TMZ-treated U87 and U251 cells markedly increased cellular proliferation; co-expression of both FoxO3a and β-catenin resulted in the highest increase. Knockdown of either FoxO3a or β-catenin in U87-TR and U251-TR cells led to a significant decrease in cell viability, which was rescued by the re-expression of FoxO3a in FoxO3a-knockdown cells. Subsequent experiments demonstrated that, in U87-TR and U251-TR cells, FoxO3a knockdown significantly reduced the protein levels of matrix metallopeptidase (MMP)9, while overexpression of FoxO3a in U87 and U251 cells enhanced the nuclear accumulation of β-catenin, concomitantly with an increase in MMP9 levels. Furthermore, MMP9 knockdown markedly reduced the levels of nuclear β-catenin. Collectively, the findings of the present study suggest that FoxO3a may regulate the nuclear accumulation of β-catenin by modulating MMP9 expression, thereby rendering glioblastoma cells resistant to TMZ, and may provide unique molecular insights into the mechanisms underlying the development of TMZ resistance in GBM.
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