ABSTRACT
It has been extensively reported that long noncoding RNAs (lncRNAs) were closely associated with multiple malignancies. The aim of our study was to investigate the effects and mechanism of lncRNA POU6F2-AS1 in lung adenocarcinoma (LADC).The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets provided us the information of LADC clinical samples. High-regulation of POU6F2-AS1 was presented in LADC tissues compared with adjacent normal tissues, which was correlated with poor outcome of LADC patients. Functional experiments in Calu-3 and NCI-H460 cells showed that POU6F2-AS1 significantly promoted LADC cell proliferation, colony formation, invasion and migration. Moreover, through online prediction, luciferase reporter assay and Pearson's correlation analysis, we found that POU6F2-AS1 may act as a competing endogenous RNA (ceRNA) of miR-34c-5p and facilitated the expression of potassium voltage-gated channel subfamily J member 4 (KCNJ4). The promoting effect of cell aggressiveness induced by POU6F2-AS1 was enhanced by KCNJ4, whilst was abrogated due to the overexpression of miR-34c-5p. Collectively, POU6F2-AS1 might function as a ceRNA through sponging miR-34c-5p to high-regulate KCNJ4 in LADC, which indicates that POU6F2-AS1 might be a promising therapeutic target with significant prognostic value for LADC treatment.
ABSTRACT
Nutlin-3 shows a potent antitumor efficacy through downregulation of the cancerogenic ether à go-go 1 (Eag1) channel. However, the molecular mechanisms responsible for the regulation of Eag1 by Nutlin-3 in cancer cells remain unclear. In this study, we propose a novel anticancer mechanism of Nutlin-3, in which Nutlin-3 acts through the p53-Eag1-PI3K/AKT pathway. We first confirmed that Eag1 was downregulated through the activation of p53 by Nutlin-3. We then revealed that the inhibition of Eag1 electrophysiological function resulted in the decrease of viability, migration and invasion of HeLa cells. It is worth noting that the antitumor effect of Nutlin-3 was abolished in the Eag1 knockdown HeLa cell lines by siRNA. And Nutlin-3 can decrease the cell viability of H8 cells which were stably transfected with Eag1, but has no obvious inhibitory effect on blank H8 cells. Finally, we demonstrated that the decrease in Eag1 channel activity induced by Nutlin-3 treatment exerts anticancer activity by inhibiting the PI3K/AKT pathway. Our study therefore fills the gap between p53 pathway and its cellular function mediated by Eag1, shedding light on the new anti-cancer mechanism of Nutlin-3.