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*

*Corresponding author for this work

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish
Pages (from-to)16462-16478
Number of pages17
JournalOncotarget
Volume7
Issue number13
DOIs
StatePublished - 29 Mar 2016

Keywords

  • Breast cancer metastasis
  • Claudin
  • EMT
  • Slug
  • miR-30a

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    Chang, C. W., Yu, J. C., Hsieh, Y. H., Yao, C. C., Chao, J-I., Chen, P. M., Hsieh, H. Y., Hsiung, C. N., Chu, H. W., Shen, C. Y., & Cheng, C. W. (2016). MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting Slug in breast cancer. Oncotarget, 7(13), 16462-16478. https://doi.org/10.18632/oncotarget.7656