miR-5003-3p promotes epithelial-mesenchymal transition in breast cancer cells through Snail stabilization and direct targeting of E-cadherin.
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.
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, The Republic of Korea.|Laboratory of Biochemistry, School of Life Sciences and Biotechnology, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 136-701, The 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, The 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, The Republic of Korea.|Laboratory of Biochemistry, School of Life Sciences and Biotechnology, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 136-701, The 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, The 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, The Republic of Korea.
Myung-Jin
MJ
Park
Laboratory of Biochemistry, School of Life Sciences and Biotechnology, Korea University, Anam-ro 145, Seongbuk-gu, Seoul 136-701, The Republic of Korea.
Joon
J
Kim
Division of Radiation Cancer Research, Korea Institute of Radiological and Medical Sciences, Nowon-gil 75, Nowon-gu, Seoul 139-706, The Republic of Korea.
Young-Hoon
YH
Han
E-cadherin; EMT; MDM2; Snail; metastasis; miR-5003-3p