MicroRNA-29b is involved in the Src-ID1 signaling pathway and is dysregulated in human lung adenocarcinoma

Oncogene. 2012 Sep 20;31(38):4221-32. doi: 10.1038/onc.2011.578. Epub 2012 Jan 16.

Abstract

The c-Src kinase regulates cancer cell invasion through inhibitor of DNA binding/differentiation 1 (ID1). Src and ID1 are frequently overexpressed in human lung adenocarcinoma. The current study aimed at identifying microRNAs (miRNAs) involved in the Src-ID1 signaling in lung cancer. Incubation of lung cancer cells with the Src inhibitor saracatinib led to the upregulation of several miRNAs including miR-29b, which was the most highly upregulated miRNA with predicted binding to the ID1 3'-untranslated region (UTR). Luciferase reporter assays confirmed direct binding of miR-29b to the ID1 3'-UTR. Expression of miR-29b suppressed ID1 levels and significantly reduced migration and invasion. Expression of antisense-miR-29b (anti-miR-29b), on the other hand, enhanced ID1 mRNA and protein levels, and significantly increased lung cancer cell migration and invasion, a hallmark of the Src-ID1 pathway. The ectopic expression of ID1 in miR-29b-overexpressing cells was able to rescue the migratory potential of these cells. Both, anti-miR-29b and ID1 overexpression diminished the effects of the Src inhibitors saracatinib and dasatinib on migration and invasion. Saracatinib and dasatinib decreased c-Myc transcriptional repression on miR-29b and led to increased ID1 protein levels, whereas forced expression of c-Myc repressed miR-29b and induced ID1. In agreement, we showed direct recruitment of c-Myc to the miR-29b promoter. miR-29b was significantly downregulated in primary lung adenocarcinoma samples compared with matched alveolar lung tissue, and miR-29b expression was a significant prognostic factor for patient outcome. These results suggest that miR-29b is involved in the Src-ID1 signaling pathway, is dysregulated in lung adenocarcinoma and is a potential predictive marker for Src kinase inhibitors.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Adenocarcinoma / genetics*
  • Adenocarcinoma / metabolism
  • Adenocarcinoma / mortality
  • Adenocarcinoma of Lung
  • Cell Line, Tumor
  • Cell Movement / genetics
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic*
  • Genes, myc
  • Humans
  • Inhibitor of Differentiation Protein 1 / genetics*
  • Inhibitor of Differentiation Protein 1 / metabolism
  • Lung Neoplasms / genetics*
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / mortality
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Prognosis
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Signal Transduction*
  • src-Family Kinases / antagonists & inhibitors
  • src-Family Kinases / genetics*
  • src-Family Kinases / metabolism

Substances

  • 3' Untranslated Regions
  • Inhibitor of Differentiation Protein 1
  • MIRN29a microRNA, human
  • MicroRNAs
  • Protein Kinase Inhibitors
  • RNA, Small Interfering
  • src-Family Kinases