In vivo NCL targeting affects breast cancer aggressiveness through miRNA regulation

• DOI: 10.1084/jem.20120950
• Publication Date: 2013-04-23T08:26:36Z
• Authors: Flavia Pichiorri; Dario Palmieri; Luciana De Luca; Jessica Consiglio; Jia You; Alberto Rocci; Tiffany Talabere; Claudia Piovan; Alessandro Lagana; Luciano Cascione; Jingwen Guan; Pierluigi Gasparini; Veronica Balatti; Gerard Nuovo; Vincenzo Coppola; Craig C. Hofmeister; Guido Marcucci; John C. Byrd; Stefano Volinia; Charles L. Shapiro; Michael A. Freitas; Carlo M. Croce
• Keywords: Guanine; Estradiol; Mice, Nude; Breast Neoplasms; Aptamers, Nucleotide; Article; 3. Good health; Gene Expression Regulation, Neoplastic; Mice; MicroRNAs; HEK293 Cells; Cell Line, Tumor; Gene Knockdown Techniques; Nucleotide; pharmacology, Breast Neoplasms; genetics/pathology, Cell Line; Tumor, Cell Proliferation, Estradiol; analogs /&/ derivatives/pharmacology, Female, Gene Expression Regulation; Neoplastic, Gene Knockdown Techniques, Gene Silencing, Genes; genetics, Guanine, HEK293 Cells, Humans, Mice, Mice; Nude, MicroRNAs; genetics/metabolism, Neoplasm Invasiveness, Neoplasm Metastasis, Oligodeoxyribonucleotides; pharmacology, Phosphoproteins; metabolism, RNA-Binding Proteins; Animals; Humans; Female; Neoplasm Invasiveness; Gene Silencing; Neoplasm Metastasis; Fulvestrant; Cell Proliferation; Genes, Neoplasm

Numerous studies have described the altered expression and the causal role of microRNAs (miRNAs) in human cancer. However, to date, efforts to modulate miRNA levels for therapeutic purposes have been challenging to implement. Here we find that nucleolin (NCL), a major nucleolar protein, posttranscriptionally regulates the expression of a specific subset of miRNAs, including miR-21, miR-221, miR-222, and miR-103, that are causally involved in breast cancer initiation, progression, and drug resistance. We also show that NCL is commonly overexpressed in human breast tumors and that its expression correlates with that of NCL-dependent miRNAs. Finally, inhibition of NCL using guanosine-rich aptamers reduces the levels of NCL-dependent miRNAs and their target genes, thus reducing breast cancer cell aggressiveness both in vitro and in vivo. These findings illuminate a path to novel therapeutic approaches based on NCL-targeting aptamers for the modulation of miRNA expression in the treatment of breast cancer.