The heterochronic microRNA let-7 inhibits cell motility by regulating the genes in the actin cytoskeleton pathway in breast cancer

Mol Cancer Res. 2013 Mar;11(3):240-50. doi: 10.1158/1541-7786.MCR-12-0432. Epub 2013 Jan 21.


The heterochronic gene let-7 serves as a tumor suppressor microRNA by targeting various oncogenic pathways in cancer cells. Considerable evidence indicates that reduced expression of let-7 might be associated with poor clinical outcome in patients with cancer. Here, we report that the expression levels of three let-7 family members, let-7a, let-7b, and let-7g, were significantly decreased in the patients with breast cancer with lymph node metastasis compared with those without lymph node metastasis. Enforced expression of let-7b significantly inhibits breast cancer cell motility and affects actin dynamics. Using bioinformatic and experimental approaches, four genes in the actin cytoskeleton pathway, including PAK1, DIAPH2, RDX, and ITGB8, were identified as let-7 direct targets. Blocking the expression of PAK1, DIAPH2, and RDX significantly inhibits breast cancer cell migration induced by let-7b repression. Our results indicate that reconstitution of let-7 expression in tumor cells could provide a novel therapeutic strategy for the treatment of metastatic disease.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Actin Cytoskeleton / metabolism*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / genetics*
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology
  • Carrier Proteins / metabolism
  • Cell Movement / genetics*
  • Cytoskeletal Proteins / metabolism
  • Female
  • Formins
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Integrins / metabolism
  • Membrane Proteins / metabolism
  • Metabolic Networks and Pathways / genetics
  • MicroRNAs / genetics
  • MicroRNAs / metabolism*
  • Neoplasm Metastasis / drug therapy
  • Neoplasm Metastasis / genetics
  • Neoplasm Metastasis / pathology
  • Signal Transduction
  • p21-Activated Kinases / metabolism


  • Carrier Proteins
  • Cytoskeletal Proteins
  • DIAPH2 protein, human
  • Formins
  • Integrins
  • Membrane Proteins
  • MicroRNAs
  • mirnlet7 microRNA, human
  • radixin
  • PAK1 protein, human
  • p21-Activated Kinases