title: miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts.
abstract: Uncontrolled cell proliferation and cytoskeletal remodeling are responsible for tumor development and ultimately metastasis. A number of studies have implicated microRNAs in the regulation of cancer cell invasion and migration. Here, we show that miR-23b regulates focal adhesion, cell spreading, cell-cell junctions and the formation of lamellipodia in breast cancer (BC), implicating a central role for it in cytoskeletal dynamics. Inhibition of miR-23b, using a specific sponge construct, leads to an increase of cell migration and metastatic spread in vivo, indicating it as a metastatic suppressor microRNA. Clinically, low miR-23b expression correlates with the development of metastases in BC patients. Mechanistically, miR-23b is able to directly inhibit a number of genes implicated in cytoskeletal remodeling in BC cells. Through intracellular signal transduction, growth factors activate the transcription factor AP-1, and we show that this in turn reduces miR-23b levels by direct binding to its promoter, releasing the pro-invasive genes from translational inhibition. In aggregate, miR-23b expression invokes a sophisticated interaction network that co-ordinates a wide range of cellular responses required to alter the cytoskeleton during cancer cell motility.
authors.affiliation: Division of Oncology, Department of Surgery and Cancer, Imperial Centre for Translational and Experimental Medicine, Imperial College, Hammersmith Hospital campus, Du Cane Road, London W12 0NN, UK.
authors.forename: Loredana
authors.initials: L
authors.lastname: Pellegrino
authors.forename: Justin
authors.initials: J
authors.lastname: Stebbing
authors.forename: Vania M
authors.initials: VM
authors.lastname: Braga
authors.forename: Adam E
authors.initials: AE
authors.lastname: Frampton
authors.forename: Jimmy
authors.initials: J
authors.lastname: Jacob
authors.forename: Lakjaya
authors.initials: L
authors.lastname: Buluwela
authors.forename: Long R
authors.initials: LR
authors.lastname: Jiao
authors.forename: Manikandan
authors.initials: M
authors.lastname: Periyasamy
authors.forename: Chris D
authors.initials: CD
authors.lastname: Madsen
authors.forename: Matthew P
authors.initials: MP
authors.lastname: Caley
authors.forename: Silvia
authors.initials: S
authors.lastname: Ottaviani
authors.forename: Laura
authors.initials: L
authors.lastname: Roca-Alonso
authors.forename: Mona
authors.initials: M
authors.lastname: El-Bahrawy
authors.forename: R Charles
authors.initials: RC
authors.lastname: Coombes
authors.forename: Jonathan
authors.initials: J
authors.lastname: Krell
authors.forename: Leandro
authors.initials: L
authors.lastname: Castellano
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D024722:Cardiac Myosins / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism*; D005260:Female; D022001:Focal Adhesions / Q000648:ultrastructure; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D035683:MicroRNAs / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D018994:Myosin Light Chains / Q000378:metabolism; D009362:Neoplasm Metastasis; D010766:Phosphorylation; D011401:Promoter Regions, Genetic; D011554:Pseudopodia / Q000648:ultrastructure; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014158:Transcription, Genetic; D054462:p21-Activated Kinases / Q000378:metabolism
chemical_list: D003598:Cytoskeletal Proteins; C552430:MIRN23a microRNA, human; D035683:MicroRNAs; D018994:Myosin Light Chains; D018808:Transcription Factor AP-1; C107184:myosin light chain 2; D054462:p21-Activated Kinases; D024722:Cardiac Myosins