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

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posted on 2023-06-09, 13:47 authored by Loredana Pellegrino, Justin Stebbing, Vania M Braga, Adam E Frampton, Jimmy Jacob, Lakjaya Buluwela, Long R Jiao, Manikandan Periyasamy, Chris D Madsen, Matthew P Caley, Silvia Ottaviani, Laura Roca-Alonso, Mona El-Bahrawy, R Charles Coombes, Jonathan Krell, Leandro CastellanoLeandro Castellano
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.

History

Publication status

  • Published

File Version

  • Published version

Journal

Nucleic Acids Research

ISSN

1362-4962

Publisher

Oxford University Press

Issue

10

Volume

41

Page range

5400-5412

Department affiliated with

  • Biochemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-06-15

First Open Access (FOA) Date

2018-06-15

First Compliant Deposit (FCD) Date

2018-06-15

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