This study was to investigate the expression correlation between long non-coding RNA metastasis-associated lung adenocarcinoma transcript 1 (lncRNA MALAT1), miR-200a-3p and programmed death-ligand 1 (PD-L1) in non-small cell lung cancer (NSCLC), and their roles in NSCLC. Real-time polymerase chain reaction (PCR) was performed to detect the expressions of MALAT1, miR-200a-3p and PD-L1 in NSCLC tissues and cells for the correlation analysis. The starBase and Targetscan databases were used to predict the binding sites between MALAT1 and miR-200a-3p, and miR-200a-3p and PD-L1, respectively. The targeting relationship between MALAT1 and miR-200a-3p, and miR-200a-3p and PD-L1 were further verified by real-time PCR and dual luciferase reporter gene assay. Cell proliferation was monitored by CCK8 and colony formation assays. The apoptosis was detected using flow cytometry. Wound healing assay and transwell assay were conducted to determine cell migration and invasion. In this study, we demonstrated that in NSCLC tissues, the expression level of MALAT1 was negatively correlated with that of miR-200a-3p, while positively correlated with PD-L1. Besides, MALAT1 promoted proliferation, mobility, migration, and invasion of NSCLC cells via sponging miR-200a-3p. PD-L1 was validated as a target of miR-200a-3p, and indirectly modulated by MALAT1. In conclusion, LncRNA MALAT1 facilitates the progression of NSCLC by modulating miR-200a-3p/PDL1 axis.
MiR-424 has been discovered to be involved in the chemoresistance of lung cancer. However, the underlying mechanism by which miR-424 played role in chemoresistance has been unknown. Here, in our study, to investigate the role of miR-424 in non-small cell lung cancer (NSCLC), we have detected the expression of miR-424-3p and -5p in NSCLC tissues and paired normal control. Moreover, to explore the role of miR-424-3p in NSCLC cells, miR-424-3p and -5p were both re-expressed and knocked down using transient transfection with their respective mimics and inhibitors. Cell viability, migration, and invasion were evaluated using MTT, wound-healing and Transwell assays, respectively. It was found that down-regulation of miR-424-3p was pronouncedly associated with NSCLC progression and overall prognosis; and that both miR-424-3p and -5p were markedly capable of preventing the proliferation, migration, and invasion in NSCLC cells. Additionally, it is miR-424-3p but not miR-424-5p that enhances the chemo-sensitivity of NSCLC cells through targeting YAP1. Mechanistically, YAP1 was identified as down-stream target of miR-424-3p. Together, it was for the first time in our study found that it is loss of miR-424-3p not miR-424-5p that enables chemoresistance through targeting YAP1 in NSCLC, supporting that miR-424-3p could be used as therapeutic target in the curing of NSCLC with chemoresistance. © 2016 Wiley Periodicals, Inc.
Tumor cells must activate specific transporters to meet their increased glutamine metabolic demands. Relative to other glutamine transporters, the ASC family transporter 2 (ASCT2, also called SLC1A5) is profoundly elevated in a wide spectrum of human cancers to coordinate metabolic reprogramming and malignant transformation. Understanding the molecular mechanisms whereby tumor cells frequently upregulate this transporter is therefore vital to develop potential strategies for transporter-targeted therapies. Combining in-silico algorithms with systemic experimental screening, we herein identify the tumor suppressor microRNA, miR-137, as an essential regulator that targets ASCT2 and cancer cell glutamine metabolism. Metabolic analysis shows that miR-137 derepression, similar to ASCT2 inactivation, significantly inhibits glutamine consumption and TCA cycle anaplerosis. Mechanistically, methyl-CpG-binding protein 2 (MeCP2) and DNA methyltransferases (DNMTs) cooperate to promote active methylation of the miR-137 promoter and inhibit its transcription, conversely reactivating ASCT2 expression and glutamine metabolism. Moreover, expression between miR-137 and ASCT2 is inversely correlated in tumor specimens from multiple cancer types, and ectopic ASCT2 expression markedly rescued miR-137 suppression of tumorigenesis. These findings thus elucidate a previously unreported mechanism responsible for ASCT2 deregulation in human cancers and identify ASCT2 as a critical downstream effector of miR-137, revealing a molecular link between DNA methylation, microRNA and tumor metabolism.
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