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The regulation of Neuropilin 1 expression by miR-338-3p promotes non-small cell lung cancer via changes in EGFR signaling.

ABSTRACT: Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for multiple extracellular ligands and typically performs growth-promoting functions in cancer cells. Accumulating evidence indicates that NRP1 is upregulated, and may be an independent predictor of cancer relapse and poor survival, in many cancer types, including non-small cell lung cancer (NSCLC). Recent evidence suggests that NRP1 affects tumour cell viability via the epidermal growth factor receptor (EGFR) and Erb-B2 receptor tyrosine kinase 2 (ErbB2) signalling pathways in venous endothelial cells and in multiple cancer cells. In the present study, we aimed to evaluate the role of NRP1 in NSCLC tumourigenesis and to explore a new post-transcriptional mechanism of NRP1 regulation via a microRNA that mediates EGFR signalling regulation in lung carcinogenesis. The results showed that miR-338-3p is poorly expressed and NRP1 is overexpressed in NSCLC tissues relative to their levels in adjacent noncancerous tissues. Luciferase reporter assays, quantitative real-time reverse transcription PCR, and Western blot analyses showed that NRP1 is a direct target of miR-338-3p. Overexpression of miR-338-3p in NSCLC cell lines inhibited cell proliferation in vitro and in vivo. Moreover, cell migration and invasion were inhibited by miR-338-3p overexpression. These effects occurred via the EGF signalling pathway. Our data revealed a new post-transcriptional mechanism by which miR-338-3p directly targets NRP1; this mechanism plays a role in enhancing drug sensitivity in EGFR wild-type patients with NSCLC.

SUBMITTER: Ding Z

PROVIDER: S-EPMC6593466 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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The regulation of Neuropilin 1 expression by miR-338-3p promotes non-small cell lung cancer via changes in EGFR signaling.

Ding Zongli Z Zhu Jianjie J Zeng Yuanyuan Y Du Wenwen W Zhang Yang Y Tang Haicheng H Zheng Yulong Y Qin Hualong H Liu Zeyi Z Huang Jian-An JA

Molecular carcinogenesis 20190227 6

Neuropilin 1 (NRP1) is a transmembrane glycoprotein that acts as a co-receptor for multiple extracellular ligands and typically performs growth-promoting functions in cancer cells. Accumulating evidence indicates that NRP1 is upregulated, and may be an independent predictor of cancer relapse and poor survival, in many cancer types, including non-small cell lung cancer (NSCLC). Recent evidence suggests that NRP1 affects tumour cell viability via the epidermal growth factor receptor (EGFR) and Erb ...[more]

PMID: 30811684

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Project description:BackgroundFerroptosis is a newly generated regulatory cell death promoted by the accumulated lipid-based reactive oxygen species (ROS). Solute carrier family 7 member 11 (SLC7A11), the cystine/glutamate antiporter, is known as a ferroptosis executor that exhibits a positive correlation with carcinoma progression because of antioxidant function. Nonetheless, it is yet unclear on the understanding of ferroptosis regulation in lung cancer.MethodsDatabase, qRT-PCR, Western-blot (WB), and immunohistochemistry were utilized to determine SLC7A11 expression and function, as well as gene iron related to necrosis in clinical tissue specimens and cells; a ferroptosis inducer, inhibitors, and SLC7A11 lentivirus were used to confirm SLC7A11's biological activity in cell viability, oxidative stress, lipid peroxidation, and iron ion enrichment in non-small cell lung cancer (NSCLC) in different cells; lentivirus was used to infect lung adenocarcinoma cell lines to acquire miR-27a-3p overexpression and knockdown cell lines, and to detect SLC7A11 level through qRT-PCR and WB. The influence of upregulated/downregulated miR-27a-3p on ferroptosis and other related biological characteristics of lung adenocarcinoma cell lines was detected.ResultsUpregulated SLC7A11 was shown in NSCLC patients and cells, and increased SLC7A11 had a relation to the poorly prognostic status of NSCLC patients. Besides, a novel miRNA, miR-27a-3p, was an essential modulator of ferroptosis via directly targeting SLC7A11 in NSCLC cells. Overexpressing miR-27a-3p led to SLC7A11 suppression via directly binding to its 3'-UTR, followed by the reduction of erastin-caused ferroptosis. In contrast, inhibited miR-27a-3p resulted in an increase in NSCLC cells' sensitivity to erastin. Of importance, the accumulated lipid ROS and cell death of iron peptide mediated by anti-miR-27a-3p can be eliminated by impeding the glutamylation process. Our literature collectively uncovered that miR-27a-3p modulated ferroptosis by targeting SLC7A11 in NSCLC cells, illustrating the important role of miRNA in ferroptosis.ConclusionMiR-27a-3p modulates ferroptosis via targeting SLC7A11 in NSCLC cells, implying the significant role of miR-27a-3p/SLC7A11 in ferroptosis.

Project description:BackgroundLong noncoding RNA small nucleolar RNA host gene 16 (lncRNA SNHG16) has been revealed to be involved in the tumorigenesis of neuroblastoma. However, the role of SNHG16 in regulating cisplatin sensitivity in neuroblastoma remains largely unknown.MethodsThe expression of SNHG16, microRNA (miR)-338-3p and polo-like kinase 4 (PLK4) mRNA was measured using quantitative real-time polymerase chain reaction. The protein levels of PLK4, multidrug resistance protein 1 (MRP1), multidrug-resistance gene 1-type p-glycoprotein (P-gp) and phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway-related proteins were detected by Western blot. The half maximal inhibitory concentration (IC50) value, cell proliferation, migration and invasion were analyzed using Cell Counting Kit-8 assays or Transwell assay. Apoptotic cells were measured by Flow cytometry. The interaction between miR-338-3p and SNHG16 or PLK4 was confirmed by dual-luciferase reporter and RNA immunoprecipitation assay. In vivo experiments were conducted through the murine xenograft model.ResultsSNHG16 was up-regulated, while miR-338-3p was down-regulated in cisplatin-resistant neuroblastoma tissues and cells. SNHG16 silencing weakened cisplatin resistance, reflected by the reduction of IC50 value, down-regulation of MRP-1 and P-gp protein expression, suppression of proliferation, migration and invasion, as well as enhancement of apoptosis in SNHG16 deletion cisplatin-resistant neuroblastoma cells. Besides that, SNHG16 could regulate PLK4 expression by sponging miR-338-3p and SNHG16/miR-338-3p/PLK4 axis could affect the activation of PI3K/AKT pathway in cisplatin-resistant neuroblastoma cells. MiR-338-3p inhibition attenuated SNHG16 deletion-mediated impairment on cisplatin resistance and PLK4 overexpression reversed the decrease of cisplatin-resistance induced by miR-338-3p re-expression. Furthermore, SNHG16 knockdown contributed to the anti-tumor effect of cisplatin in neuroblastoma in vivo.ConclusionSNHG16 contributed to the tumorigenesis and cisplatin resistance in neuroblastoma possibly through miR-338-3p/PLK4 pathway, indicating a novel insight for overcoming chemoresistance in neuroblastoma patients.

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The regulation of Neuropilin 1 expression by miR-338-3p promotes non-small cell lung cancer via changes in EGFR signaling.

Publications

The regulation of Neuropilin 1 expression by miR-338-3p promotes non-small cell lung cancer via changes in EGFR signaling.

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