MiR-124 targets Slug to regulate epithelial-mesenchymal transition and metastasis of breast cancer

Carcinogenesis. 2013 Mar;34(3):713-22. doi: 10.1093/carcin/bgs383. Epub 2012 Dec 17.

Abstract

MicroRNAs (miRNAs or miR) have been integrated into tumorigenic programs as either oncogenes or tumor suppressor genes. The miR-124 was reported to be attenuated in several tumors, such as glioma, medulloblastoma and hepatocellular carcinoma. However, its role in cancer remains greatly elusive. In this study, we show that the miR-124 expression is significantly suppressed in human breast cancer specimens, which is reversely correlated to histological grade of the cancer. More intriguingly, ectopic expression of miR-124 in aggressive breast cancer cell lines MDA-MB-231 and BT-549 strongly inhibits cell motility and invasive capacity, as well as the epithelial-mesenchymal transition process. Also, lentivirus-delivered miR-124 endows MDA-MB-231 cells with the ability to suppress cell colony formation in vitro and pulmonary metastasis in vivo. Further studies have identified the E-cadherin transcription repressor Slug as a direct target gene of miR-124; its downregulation by miR-124 increases the expression of E-cadherin, a hallmark of epithelial cells and a repressor of cell invasion and metastasis. Moreover, knockdown of Slug notably impairs the motility of MDA-MB-231 cells, whereas re-expression of Slug abrogates the reduction of motility and invasion ability induced by miR-124 in MDA-MB-231 cells. These findings highlight an important role for miR-124 in the regulation of invasive and metastatic potential of breast cancer and suggest a potential application of miR-124 in cancer treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Base Sequence
  • Binding Sites
  • Breast Neoplasms / metabolism
  • Breast Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Movement
  • Cell Shape
  • Down-Regulation
  • Epithelial-Mesenchymal Transition*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Genes, Reporter
  • Humans
  • Luciferases, Renilla / biosynthesis
  • Luciferases, Renilla / genetics
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / secondary*
  • Mice
  • Mice, SCID
  • MicroRNAs / genetics
  • MicroRNAs / metabolism
  • MicroRNAs / physiology*
  • Neoplasm Invasiveness
  • Neoplasm Transplantation
  • RNA Interference
  • Snail Family Transcription Factors
  • Transcription Factors / genetics*
  • Transcription Factors / metabolism
  • Transcription Factors / physiology
  • Tumor Burden

Substances

  • 3' Untranslated Regions
  • MIRN124 microRNA, human
  • MicroRNAs
  • SNAI1 protein, human
  • Snai2 protein, mouse
  • Snail Family Transcription Factors
  • Transcription Factors
  • Luciferases, Renilla