Pim-1 kinase is a target of miR-486-5p and eukaryotic translation initiation factor 4E, and plays a critical role in lung cancer

Abstract

BackgroundPim-1 kinase is a proto-oncogene and its dysregulation contributes to tumorigenesis and progression of a variety of malignancies. Pim-1 was suggested as a therapeutic target of cancers. The functional relevance of Pim-1 and the mechanism underlying its dysregulation in lung tumorigenesis remained unclear. This study aimed to investigate if Pim-1 has important functions in non-small-cell lung cancer (NSCLC) by: 1) evaluating the clinicopathologic significance of Pim-1 through analysing its expression in 101 human NSCLCs tissues using quantitative PCR, Western Blot and immunohistochemical studies, 2) determining its role in NSCLC and drug resistance using in vitro assays, and 3) investigating the regulatory mechanism of Pim-1 dysregulation in lung tumorigenesis.ResultsPim-1 was upregulated in 66.2% of the lung tumor tissues and its expression was significantly related to advanced stage (P = 0.019) and lymph node metastasis (P = 0.026). Reduced Pim-1 expression suppressed NSCLC cell growth, cell cycle progression and migration in vitro. Pim-1 was a novel target of miR-486-5p determined by luciferase report assay, and ectopic miR-486-5p expression in cancer cells reduced Pim-1 expression. Furthermore, eukaryotic translation initiation factor 4E (eIF4E) controlled the synthesis of Pim-1 in NSCLC cells, and its expression was positively associated with that of Pim-1 in NSCLC tissue specimens (r = 0.504, p < 0.001). The downregulated miR-486-5p and upregulated eIF4E in NSCLC cells led to the overexpression of Pim-1 by relieving the inhibitory effect of the 3′-UTR or 5′-UTR of Pim-1 mRNA, respectively. Moreover, Pim-1 knockdown sensitized NSCLC cells to cisplatin and EGFR tyrosine kinase inhibitor, gefitinib.ConclusionsPim-1 kinase could be a critical survival signaling factor in NSCLC, and regulated by miR-486-5p and eIF4E. Pim-1 kinase may provide a potential target for diagnosis and treatment for lung cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/1476-4598-13-240) contains supplementary material, which is available to authorized users.

Expression profile analysis of microRNAs and downregulated miR-486-5p and miR-30a-5p in non-small cell lung cancer

“…miR-486 is located on one of the most frequent genomic rearrangement regions, chromosome 8p11.21, which contains potential tumor-suppressor genes in lung tumorigenesis. Recent findings have shown miR-486-5p plays a critical role in breast and lung cancer by targeted PIM-1 (41,42). The results from the present study are consistent with those of previous findings, suggesting that miR-486-5p is a potential tumor suppressor in carcinogenesis.…”

ANK1 Methylation regulates expression of MicroRNA-486-5p and discriminates lung tumors by histology and smoking status

“…1A). Although miR-486-5p down-regulation and its effects in promoting lung carcinogenesis have been previously reported [3,8–10], the mechanism of repression is unknown. MicroRNAome analysis of NSCLC cell lines treated with vehicle or DAC as described [33] showed that DAC treatment increased miR-486-5p expression in 5/10 cell lines with lowest expression by 2 to 8-fold (Fig.…”

“…MiR-486-5p is a tumor-suppressor miR that is often down-regulated across multiple malignancies including lung [3,4], gastric [5], pancreatic [6], and other [7] cancers. In vitro and laboratory animal based gain- or loss-of-function studies on miR-486-5p have confirmed its role in suppressing the growth of lung cancer [8–10]. Reduced miR-486-5p expression strongly contribute to lung cancer progression while recent studies showed that it could be reliably detected in easily accessible samples such as serum and sputum indicating its potential as a prognostic biomarker.…”

Toward the promise of microRNAs – Enhancing reproducibility and rigor in microRNA research

“…10,11 microRNAs miR-451a and miR-144 have yet to be identified in any non-neoplastic cell type, yet they repeatedly are assigned non-RBC functionality due to tissue level data being confused for cell level expression data (Tables 1 and 2). 12-17 miR-486 is also abundant in platelets, but neither RBC nor platelet expression justifies its assigned role in a variety of disease states in which it is unlikely to participate. 18,19 Thus it is important to identify the cellular source of a tissue-level microRNA signature, which can be done by checking known datasets, 5,20 obtaining cell-specific data from the Sequence Read Archive or Gene Expression Omnibus, or measuring the microRNA by qPCR or northern blot in a cell type of interest.…”