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

Nucleic Acids Res. 2013 May 1;41(10):5400-12. doi: 10.1093/nar/gkt245. Epub 2013 Apr 10.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cardiac Myosins / metabolism
  • Cell Adhesion
  • Cell Line
  • Cell Line, Tumor
  • Cell Movement* / genetics
  • Cytoskeletal Proteins / genetics
  • Cytoskeletal Proteins / metabolism
  • Cytoskeleton / metabolism*
  • Female
  • Focal Adhesions / ultrastructure
  • Gene Expression Regulation, Neoplastic*
  • Humans
  • Mice
  • Mice, Nude
  • MicroRNAs / antagonists & inhibitors
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Myosin Light Chains / metabolism
  • Neoplasm Metastasis
  • Phosphorylation
  • Promoter Regions, Genetic
  • Pseudopodia / ultrastructure
  • Transcription Factor AP-1 / metabolism
  • Transcription, Genetic
  • p21-Activated Kinases / metabolism

Substances

  • Cytoskeletal Proteins
  • MIRN23a microRNA, human
  • MicroRNAs
  • Myosin Light Chains
  • Transcription Factor AP-1
  • myosin light chain 2
  • p21-Activated Kinases
  • Cardiac Myosins