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

• Published in: Oncotarget 2016-03, Vol.7 (13), p.16462-16478
• Main Authors: Chang, Chia-Wei, Yu, Jyh-Cherng, Hsieh, Yi-Hsien, Yao, Chung-Chin, Chao, Jui-I, Chen, Po-Ming, Hsieh, Hsiao-Yen, Hsiung, Chia-Ni, Chu, Hou-Wei, Shen, Chen-Yang, Cheng, Chun-Wen
• Format: Article
• Language: English
• Subjects: 3' Untranslated Regions - genetics; Animals; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Cell Line; Cell Line, Tumor; Claudins - genetics; Claudins - metabolism; Epithelial-Mesenchymal Transition - genetics; Female; Gene Expression Regulation, Neoplastic; Humans; MCF-7 Cells; Mice, Inbred BALB C; Mice, Nude; MicroRNAs - genetics; Microscopy, Confocal; Neoplasm Metastasis; Research Paper; Snail Family Transcription Factors - genetics; Snail Family Transcription Factors - metabolism; Tight Junction Proteins - genetics; Tight Junction Proteins - metabolism; Transplantation, Heterologous
• ISSN: 1949-2553; 1949-2553
• DOI: 10.18632/oncotarget.7656

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.