title: MicroRNA-30a increases tight junction protein expression to suppress the epithelial-mesenchymal transition and metastasis by targeting Slug in breast cancer.
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.
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Chia-Wei
authors.initials: CW
authors.lastname: Chang
authors.affiliation: Department of Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan.
authors.forename: Jyh-Cherng
authors.initials: JC
authors.lastname: Yu
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Yi-Hsien
authors.initials: YH
authors.lastname: Hsieh
authors.affiliation: Department of Surgery, Chung Shan Medical University Hospital, Taichung, Taiwan.
authors.forename: Chung-Chin
authors.initials: CC
authors.lastname: Yao
authors.affiliation: Department of Biological Science and Technology, National Chiao Tung University, Hsinchu, Taiwan.
authors.forename: Jui-I
authors.initials: JI
authors.lastname: Chao
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Po-Ming
authors.initials: PM
authors.lastname: Chen
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.
authors.forename: Hsiao-Yen
authors.initials: HY
authors.lastname: Hsieh
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Chia-Ni
authors.initials: CN
authors.lastname: Hsiung
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.
authors.forename: Hou-Wei
authors.initials: HW
authors.lastname: Chu
authors.affiliation: Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan.|College of Public Health, China Medical University, Taichung, Taiwan.
authors.forename: Chen-Yang
authors.initials: CY
authors.lastname: Shen
authors.affiliation: Institute of Biochemistry, Microbiology and Immunology, Chung Shan Medical University, Taichung, Taiwan.|Clinical Laboratory, Chung Shan Medical University Hospital, Taichung, Taiwan, Taiwan.
authors.forename: Chun-Wen
authors.initials: CW
authors.lastname: Cheng
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D045744:Cell Line, Tumor; D057167:Claudins / Q000235:genetics / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D061986:MCF-7 Cells; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics*; D018613:Microscopy, Confocal; D009362:Neoplasm Metastasis; D000071250:Snail Family Transcription Factors / Q000235:genetics* / Q000378:metabolism; D062725:Tight Junction Proteins / Q000235:genetics* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D020413:3' Untranslated Regions; D057167:Claudins; C546086:MIRN30b microRNA, human; D035683:MicroRNAs; C000604407:SNAI1 protein, human; D000071250:Snail Family Transcription Factors; D062725:Tight Junction Proteins
keywords: EMT; breast cancer metastasis; claudin; miR-30a; slug