miR-181b-3p promotes epithelial–mesenchymal transition in breast cancer cells through Snail stabilization by directly targeting YWHAG

• Published in: Biochimica et biophysica acta 2016-07, Vol.1863 (7), p.1601-1611
• Main Authors: Yoo, Je-Ok, Kwak, Seo-Young, An, Hyun-Ju, Bae, In-Hwa, Park, Myung-Jin, Han, Young-Hoon
• Format: Article
• Language: English
• Subjects: 14-3-3 Proteins - genetics; 14-3-3 Proteins - metabolism; 3' Untranslated Regions; Animals; Binding Sites; Breast Neoplasms - enzymology; Breast Neoplasms - genetics; Breast Neoplasms - pathology; Cell Movement; EMT; Epithelial-Mesenchymal Transition; Female; Gene Expression Regulation, Enzymologic; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms - enzymology; Lung Neoplasms - genetics; Lung Neoplasms - secondary; MCF-7 Cells; Metastasis; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; MicroRNAs - metabolism; miR-181b-3p; Neoplasm Invasiveness; Phenotype; Protein Stability; Signal Transduction; Snail; Snail Family Transcription Factors; Time Factors; Transcription Factors - genetics; Transcription Factors - metabolism; Transfection; YWHAG
• ISSN: 0167-4889; 0006-3002; 1879-2596
• DOI: 10.1016/j.bbamcr.2016.04.016

Epithelial–mesenchymal transition (EMT) is essential for increased invasion and metastasis during cancer progression. Among the candidate EMT-regulating microRNAs that we previously identified, miR-181b-3p was found to induce EMT in MCF7 breast cancer cells, as indicated by an EMT-characteristic morphological change, increased invasiveness, and altered expression of an EMT marker. Transfection with a miR-181b-3p inhibitor reduced the expression of mesenchymal markers and the migration and invasion of highly invasive breast cancer cells. miR-181b-3p induced the upregulation of Snail, a master EMT inducer and transcriptional repressor of E-cadherin, through protein stabilization. YWHAG was identified as a direct target of miR-181b-3p, downregulation of which induced Snail stabilization and EMT phenotypes. Ectopic expression of YWHAG abrogated the effect of miR-181b-3p, including Snail stabilization and the promotion of invasion. In situ hybridization and immunohistochemical analyses indicated that YWHAG expression was inversely correlated with the expression of miR-181b-3p and Snail in human breast cancer tissues. Furthermore, transfection with miR-181b-3p increased the frequency of metastatic nodule formation in the lungs of mice in experimental metastasis assays using MDA-MB-231 cells. Taken together, our data suggest that miR-181b-3p functions as a metastasis activator by promoting Snail-induced EMT, and may therefore be a therapeutic target in metastatic cancers. [Display omitted] •miR-181b-3p induces EMT in breast cancer cells.•miR-181b-3p-induced EMT is through Snail stabilization by directly targeting YWHAG.•miR-181b-3p expression is induced by TGFβ and contributes to TGFβ-induced EMT.•miR-181b-3p promotes metastasis of breast cancer cells to the lung in vivo.