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Biochim Biophys Acta. 2016 Jul;1863(7 Pt A):1601-11. doi: 10.1016/j.bbamcr.2016.04.016. Epub 2016 Apr 18.

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

Author information

1
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, Republic of Korea.
2
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, Republic of Korea; Laboratory of Biochemistry, School of Life Sciences and Biotechnology, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 136-701, Republic of Korea.
3
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, Republic of Korea. Electronic address: yhhan@kirams.re.kr.

Abstract

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.

KEYWORDS:

EMT; Metastasis; Snail; YWHAG; miR-181b-3p

PMID:
27102539
DOI:
10.1016/j.bbamcr.2016.04.016
[Indexed for MEDLINE]
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