Oncotarget

Research Papers:

MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting Slug in breast cancer

Chia-Wei Chang, Jyh-Cherng Yu, Yi-Hsien Hsieh, Chung-Chin Yao, Jui-I Chao, Po-Ming Chen, Hsiao-Yen Hsieh, Chia-Ni Hsiung, Hou-Wei Chu, Chen-Yang Shen & Chun-Wen Cheng _

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Oncotarget. 2016; 7:16462-16478. https://doi.org/10.18632/oncotarget.7656

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Abstract

Chia-Wei Chang1, Jyh-Cherng Yu2, Yi-Hsien Hsieh1, Chung-Chin Yao3, Jui-I Chao4, Po-Ming Chen1, Hsiao-Yen Hsieh1, Chia-Ni Hsiung5, Hou-Wei Chu5, Chen-Yang Shen5,6, Chun-Wen Cheng1,7

1Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan

2Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan

3Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan

4Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan

5Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan

6College of Public Health, China Medical University, Taichung, Taiwan

7Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan

Correspondence to:

Chun-Wen Cheng, e-mail: cwcheng@csmu.edu.tw

Chen-Yang Shen, e-mail: bmcys@ibms.sinica.edu.tw

Keywords: breast cancer metastasis, EMT, miR-30a, slug, claudin

Received: August 07, 2015     Accepted: February 10, 2016     Published: February 24, 2016

ABSTRACT

The epithelial-to-mesenchymal (EMT) transition is a prerequisite for conferring metastatic potential during tumor progression. microRNA-30a (miR-30a) expression was significantly lower in aggressive breast cancer cell lines compared with non-invasive breast cancer and non-malignant mammary epithelial cell lines. In contrast, miR-30a overexpression reversed the mesenchymal appearance of cancer cells to result in a cobblestone-like epithelial phenotype. We identified Slug, one of the master regulators of EMT, as a target of miR-30a using in silico prediction. Reporter assays indicated that miR-30a could bind to the 3'-untranslted region of Slug mRNA. Furthermore, we linked miR-30a to increased expression of claudins, a family of tight junction transmembrane proteins. An interaction between Slug and E-box in the claudin promoter sequences was reduced upon miR-30a overexpression, further leading to reduction of filopodia formation and decreased invasiveness/metastasis capabilities of breast cancer cells. Consistently, delivery of miR-30a in xenografted mice decreased tumor invasion and migration. In patients with breast cancer, a significantly elevated risk of the miR-30alow/CLDN2low/FSCNhigh genotype was observed, linking to a phenotypic manifestation of larger tumor size, lymph node metastasis, and advanced tumor stage among patients. In conclusion, the miR-30a/Slug axis inhibits mesenchymal tumor development by interfering with metastatic cancer cell programming and may be a potential target for therapy in breast cancer.


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