title: Unregulated miR-96 induces cell proliferation in human breast cancer by downregulating transcriptional factor FOXO3a.
abstract: FOXO transcription factors are key tumor suppressors in mammalian cells. Until now, suppression of FOXOs in cancer cells was thought to be mainly due to activation of multiple onco-kinases by a phosphorylation-ubiquitylation-mediated cascade. Therefore, it was speculated that inhibition of FOXO proteins would naturally occur through a multiple step post-translational process. However, whether cancer cells may downregulate FOXO protein via an alternative regulatory mechanism is unclear. In the current study, we report that expression of miR-96 was markedly upregulated in breast cancer cells and breast cancer tissues compared with normal breast epithelial cells (NBEC) and normal breast tissues. Ectopic expression of miR-96 induced the proliferation and anchorage-independent growth of breast cancer cells, while inhibition of miR-96 reduced this effect. Furthermore, upregulation of miR-96 in breast cancer cells resulted in modulation of their entry into the G1/S transitional phase, which was caused by downregulation of cyclin-dependent kinase (CDK) inhibitors, p27(Kip1) and p21(Cip1), and upregulation of the cell-cycle regulator cyclin D1. Moreover, we demonstrated that miR-96 downregulated FOXO3a expression by directly targeting the FOXO3a 3'-untranslated region. Taken together, our results suggest that miR-96 may play an important role in promoting proliferation of human breast cancer cells and present a novel mechanism of miRNA-mediated direct suppression of FOXO3a expression in cancer cells.
authors.affiliation: State Key Laboratory of Oncology in Southern China, Department of Experimental Research, Cancer Center, Sun Yat-sen University, Guangzhou, China.
authors.forename: Huanxin
authors.initials: H
authors.lastname: Lin
authors.forename: Ting
authors.initials: T
authors.lastname: Dai
authors.forename: Huaping
authors.initials: H
authors.lastname: Xiong
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Zhao
authors.forename: Xiuting
authors.initials: X
authors.lastname: Chen
authors.forename: Chunping
authors.initials: C
authors.lastname: Yu
authors.forename: Jun
authors.initials: J
authors.lastname: Li
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.forename: Libing
authors.initials: L
authors.lastname: Song
mesh_terms: D020413:3' Untranslated Regions; D001940:Breast / Q000378:metabolism; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D018450:Disease Progression; D015536:Down-Regulation; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020413:3' Untranslated Regions; C493956:CDKN1A protein, human; C436291:CDKN1B protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C541492:MIRN96 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D050760:Cyclin-Dependent Kinase Inhibitor p27