miR-212 Increases Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Sensitivity in Non-Small Cell Lung Cancer by Targeting the Antiapoptotic Protein PED
ABSTRACT PED/PEA-15 (PED) is a death effector domain family member of 15 kDa with a broad antiapoptotic function found overexpressed in a number of different human tumors, including lung cancer. To date, the mechanisms that regulate PED expression are unknown. Therefore, we address this point by the identification of microRNAs that in non-small cell lung cancer (NSCLC) modulate PED levels. In this work, we identify miR-212 as a negative regulator of PED expression. We also show that ectopic expression of this miR increases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced cell death in NSCLC cells. In contrast, inhibition of endogenous miR-212 by use of antago-miR results in increase of PED protein expression and resistance to TRAIL treatment. Besides, in NSCLC, we show both in vitro and in vivo that PED and miR-212 expressions are inversely correlated, that is, PED is upregulated and miR-212 is rarely expressed. In conclusion, these findings suggest that miR-212 should be considered as a tumor suppressor because it negatively regulates the antiapoptotic protein PED and regulates TRAIL sensitivity.
SourceAvailable from: Sergey Rykov[Show abstract] [Hide abstract]
ABSTRACT: Interaction between microRNA (miRNA) and messenger RNA of target genes at the posttranscriptional level provides fine-tuned dynamic regulation of cell signaling pathways. Each miRNA can be involved in regulating hundreds of protein-coding genes, and, conversely, a number of different miRNAs usually target a structural gene. Epigenetic gene inactivation associated with methylation of promoter CpG-islands is common to both protein-coding genes and miRNA genes. Here, data on functions of miRNAs in development of tumor-cell phenotype are reviewed. Genomic organization of promoter CpG-islands of the miRNA genes located in inter- and intragenic areas is discussed. The literature and our own results on frequency of CpG-island methylation in miRNA genes from tumors are summarized, and data regarding a link between such modification and changed activity of miRNA genes and, consequently, protein-coding target genes are presented. Moreover, the impact of miRNA gene methylation on key oncogenetic processes as well as affected signaling pathways is discussed.Biochemistry (Moscow) 02/2015; 80(2):145-162. DOI:10.1134/S0006297915020029 · 1.35 Impact Factor
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ABSTRACT: Lung cancer is the leading cause of cancer-related mortality worldwide. microRNAs (miRNAs) are small post-transcriptional regulatory non-coding RNAs that function as oncogenes or tumor suppressors in human cancers. Emerging evidence reveals that deregulation of miRNAs contributes to the progression of human lung cancer, which is the leading cause of cancer-related deaths worldwide. In the present study, we found that upregulation of the miR-212/132 cluster significantly suppressed the growth and focus formation of A549 and H1299 cells. Moreover, forced expression of this cluster conferred radiosensitivity and inhibited the migration of lung cancer cells, whereas downregulation of miR-212/132 reversed the above effects. Furthermore, miR-212/132 overexpression induced cell cycle arrest at the G1/S phase transition of the lung cancer cells, and inhibition of miR-132 and miR-212 abrogated this arrest. In addition, miR-212/132 overexpression increased the percentage of cells undergoing apoptosis. Cells transfected with the miR-212/132 cluster exhibited upregulated p21 expression and reduced cyclin D1 expression. Conversely, cells transfected with the miR-212/132 inhibitor showed reduced expression of p21 and upregulated expression of cyclin D1, suggesting that miR-212/132 may mediate proliferation and cell cycle arrest through p21 and cyclin D1. Our study provides insight into the biological function of the miR-212/132 cluster in lung cancer. The present study may provide a potential therapeutic target for the treatment of lung cancer.Oncology Reports 12/2014; 33(2). DOI:10.3892/or.2014.3637 · 2.19 Impact Factor
06/2012; 1(2):158-9. DOI:10.3978/j.issn.2218-6751.2012.02.03