MicroRNA-1 targets Slug and endows lung cancer A549 cells with epithelial and anti-tumorigenic properties

• Published in: Experimental cell research Vol. 319; no. 3; pp. 77 - 88
• Main Authors: Tominaga, Eiji, Yuasa, Katsutoshi, Shimazaki, Sho, Hijikata, Takao
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2013; Elsevier BV
• Subjects: A549 cells; Adenocarcinoma - genetics; Adenocarcinoma - pathology; Adherens junction; Base Sequence; Cell Line, Tumor; Cell Movement - genetics; Cell Proliferation; Cellular biology; E-cadherin; Epithelial Cells - metabolism; Epithelial Cells - pathology; Epithelial-Mesenchymal Transition - genetics; Gene expression; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor - physiology; Genotype & phenotype; Humans; Lung cancer; Lung Neoplasms - genetics; Lung Neoplasms - pathology; MicroRNAs - genetics; MicroRNAs - metabolism; MicroRNAs - physiology; miR-1; Neoplasm Invasiveness; Ribonucleic acid; RNA; RNA Interference; Slug; Snail Family Transcription Factors; Transcription Factors - antagonists & inhibitors; Transcription Factors - genetics; Transfection; Tumors; miR-1; A549 cells; Slug; E-cadherin; Adherens junction
• ISSN: 0014-4827; 1090-2422
• DOI: 10.1016/j.yexcr.2012.10.015

MicroRNA-1 (miR-1) has recently been suggested to function as a tumor suppressor. Its functional relevance was assessed by exploring structural and tumorigenic properties of lung cancer A549 cells stably transduced with retrovirus containing pre-miR-1. A549 cells overexpressing miR-1 exhibited a significant morphological change from a mesenchymal to an epithelial phenotype characterized by cell polarization and intercellular junctions. The cells showed increased expression of E-cadherin, which colocalized with cortical actin filaments and vinculin to form typical adherens junction at the apical regions of intercellular borders. Additionally, they exhibited occludin-positive tight junctions at similar apical regions. Moreover, their migratory and invasive activities were inhibited, and their sensitivity to doxorubicin was increased slightly compared to control mock-infected cells. These structural and tumorigenic properties induced by miR-1 were associated with the reduced expression of Slug, which was a transcriptional repressor of E-cadherin or an inducer of epithelial-to-mesenchymal transition. Consistently, Slug was identified as a miR-1 target by bioinformatics and a luciferase reporter assay with plasmids containing luciferase-Slug 3′UTR. Collectively, the data presented here suggest that re-expression of miR-1 may be an effective therapy that prevents cancer malignancy by converting cells from a mesenchymal phenotype to an epithelial phenotype via the downregulation of Slug. ► MiR-1 overexpression promotes the formation of adherens and tight junctions. ► MiR-1 overexpression restores the apico-basal polarity of cells. ► MiR-1 may convert cells from a mesenchymal to an epithelial phenotype. ► MiR-1 enhances E-cadherin promoter activity possibly by Slug downregulation. ► Anti-tumorigenic effects of miR-1 may correlate with its downregulation of Slug.