miR-181b-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization by directly targeting YWHAG.
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.
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, Republic of Korea.
Je-Ok
JO
Yoo
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.
Seo-Young
SY
Kwak
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.
Hyun-Ju
HJ
An
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, Republic of Korea.
In-Hwa
IH
Bae
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, Republic of Korea.
Myung-Jin
MJ
Park
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.
Young-Hoon
YH
Han
D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism*; D020413:3' Untranslated Regions; D000818:Animals; D001665:Binding Sites; D001943:Breast Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D002465:Cell Movement; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000235:genetics / Q000556:secondary; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D055550:Protein Stability; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D048948:14-3-3 Proteins; D020413:3' Untranslated Regions; C540193:MIrn181 microRNA, human; D035683:MicroRNAs; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; C000610447:YWHAG protein, human
EMT; Metastasis; Snail; YWHAG; miR-181b-3p