Gain of miR-151 on chromosome 8q24.3 facilitates tumour cell migration and spreading through downregulating RhoGDIA

Nat Cell Biol. 2010 Apr;12(4):390-9. doi: 10.1038/ncb2039. Epub 2010 Mar 21.

Abstract

Recurrent chromosomal aberrations are often observed in hepatocellular carcinoma (HCC), but little is known about the functional non-coding sequences, particularly microRNAs (miRNAs), at the chromosomal breakpoints in HCC. Here we show that 22 miRNAs are often amplified or deleted in HCC. MicroRNA-151 (miR-151), a frequently amplified miRNA on 8q24.3, is correlated with intrahepatic metastasis of HCC. We further show that miR-151, which is often expressed together with its host gene FAK, encoding focal adhesion kinase, significantly increases HCC cell migration and invasion in vitro and in vivo, mainly through miR-151-5p, but not through miR-151-3p. Moreover, miR-151 exerts this function by directly targeting RhoGDIA, a putative metastasis suppressor in HCC, thus leading to the activation of Rac1, Cdc42 and Rho GTPases. In addition, miR-151 can function synergistically with FAK to enhance HCC cell motility and spreading. Thus, our findings indicate that chromosome gain of miR-151 is a crucial stimulus for tumour invasion and metastasis of HCC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 3' Untranslated Regions
  • Animals
  • Carcinoma, Hepatocellular / genetics*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / secondary
  • Cell Movement*
  • Cell Shape*
  • Chromosome Breakpoints
  • Chromosomes, Human, Pair 8*
  • Focal Adhesion Kinase 1 / genetics
  • Focal Adhesion Kinase 1 / metabolism
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Guanine Nucleotide Dissociation Inhibitors / metabolism*
  • Hep G2 Cells
  • Humans
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Mice
  • Mice, Nude
  • MicroRNAs / metabolism*
  • Neoplasm Invasiveness
  • Signal Transduction / genetics
  • Transduction, Genetic
  • Transfection
  • Transplantation, Heterologous
  • cdc42 GTP-Binding Protein / genetics
  • cdc42 GTP-Binding Protein / metabolism
  • rac1 GTP-Binding Protein / genetics
  • rac1 GTP-Binding Protein / metabolism
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors

Substances

  • 3' Untranslated Regions
  • Guanine Nucleotide Dissociation Inhibitors
  • MIRN151a microRNA, human
  • MicroRNAs
  • RAC1 protein, human
  • rho-Specific Guanine Nucleotide Dissociation Inhibitors
  • Focal Adhesion Kinase 1
  • PTK2 protein, human
  • cdc42 GTP-Binding Protein
  • rac1 GTP-Binding Protein