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MicroRNA-381 Represses ID1 and is Deregulated in Lung Adenocarcinoma

Introduction: MicroRNAs are small, noncoding RNAs that suppress gene expression by binding to the 3’ untranslated region (UTR) and thereby repress translation or decrease messenger RNA stability. Inhibitor of differentiation 1 (ID1) is a putative stem-cell gene involved in invasion and angiogenesis. We previously showed that ID1 is regulated by Src kinases, overexpressed in human lung adenocarcinoma, and targeted by Src-dependent microRNAs. The current study focused on the association between miR-381 and ID1 in lung adenocarcinoma. Methods: An ID1 3’UTR-luciferase reporter assay was used to determine whether miR-381 directly targets ID1. Human lung cancer cell lines were stably transduced with a precursor of miR-381 to evaluate its role on ID1 expression and to investigate changes in cell migration and invasion. The Src tyrosine kinase inhibitors saracatinib and dasatinib were used to repress ID1 expression. MiR-381 expression was measured in 18 human lung adenocarcinomas and corresponding normal lung tissue by quantitative reverse-transcription polymerase chain reaction. Results: ID1 is a direct target of miR-381 as shown by 3’UTR luciferase reporter assays. MiR-381 expression was negatively correlated with ID1 expression in lung cancer cell lines. Ectopic expression of miR-381 reduced ID1 mRNA and protein levels, and significantly decreased cell migration and invasion. Furthermore, miR-381 was significantly downregulated in human lung adenocarcinomas, and low miR-381 expression levels correlated with poor prognosis. Conclusion: These results suggest that downregulation of miR-381 and thus induction of its target ID1 may contribute to the metastatic potential of lung adenocarcinomas. Further studies to explore potential therapeutic strategies, including Src inhibitors, are ongoing.