miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts

Pellegrino, Loredana, Stebbing, Justin, Braga, Vania M, Frampton, Adam E, Jacob, Jimmy, Buluwela, Lakjaya, Jiao, Long R, Periyasamy, Manikandan, Madsen, Chris D, Caley, Matthew P, Ottaviani, Silvia, Roca-Alonso, Laura, El-Bahrawy, Mona, Coombes, R Charles, Krell, Jonathan and Castellano, Leandro (2013) miR-23b regulates cytoskeletal remodeling, motility and metastasis by directly targeting multiple transcripts. Nucleic Acids Research, 41 (10). pp. 5400-5412. ISSN 1362-4962

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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.

Item Type: Article
Schools and Departments: School of Life Sciences > Biochemistry
Depositing User: Leandro Castellano
Date Deposited: 15 Jun 2018 12:32
Last Modified: 02 Jul 2019 15:30
URI: http://sro.sussex.ac.uk/id/eprint/76534

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