miR-5003-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization and direct targeting of E-cadherin
- Authors
- Kwak, Seo-Young; Yoo, Je-Ok; An, Hyun-Ju; Bae, In-Hwa; Park, Myung-Jin; Kim, Joon; Han, Young-Hoon
- Issue Date
- 10월-2016
- Publisher
- OXFORD UNIV PRESS
- Keywords
- miR-5003-3p; EMT; metastasis; E-cadherin; Snail; MDM2
- Citation
- JOURNAL OF MOLECULAR CELL BIOLOGY, v.8, no.5, pp.372 - 383
- Indexed
- SCIE
SCOPUS
- Journal Title
- JOURNAL OF MOLECULAR CELL BIOLOGY
- Volume
- 8
- Number
- 5
- Start Page
- 372
- End Page
- 383
- URI
- https://scholar.korea.ac.kr/handle/2021.sw.korea/87349
- DOI
- 10.1093/jmcb/mjw026
- ISSN
- 1674-2788
- Abstract
- One of the initial steps in metastatic dissemination is the epithelial-mesenchymal transition (EMT). Along this line, microRNAs (miRNAs) have been shown to function as important regulators of tumor progression at various stages. Therefore, we performed a functional screening for EMT-regulating miRNAs and identified several candidate miRNAs. Among these, we demonstrated that miR-5003-3p induces cellular features characteristic of EMT. miR-5003-3p induced upregulation of Snail, a key EMT-promoting transcription factor and transcriptional repressor of E-cadherin, through protein stabilization. MDM2 was identified as a direct target of miR-5003-3p, the downregulation of which induced Snail stabilization. E-cadherin was also demonstrated to be a direct target of miR-5003-3p, reinforcing the EMT-promoting function of miR-5003-3p. In situ hybridization and immunohistochemical analyses using tissue microarrays revealed that miR-5003-3p expression was higher in paired metastatic breast carcinoma tissues than in primary ductal carcinoma tissues, and was inversely correlated with the expression of MDM2 and E-cadherin. Furthermore, miR-5003-3p enhanced the formation of metastatic nodules in the lungs of mice in a tail vein injection experiment. Collectively, our results suggest that miR-5003-3p functions as a metastasis activator by promoting EMT through dual regulation of Snail stability and E-cadherin, and may therefore be a potential therapeutic target in metastatic cancers.
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