GEF-H1 over-expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signalling

J Pathol. 2012 Dec;228(4):575-85. doi: 10.1002/path.4084. Epub 2012 Sep 28.


The interstitial chromosome (chr.) 1q21-q22 region is frequently amplified in human cancers, where it has been reported to carry prognostic significance for patients. We attempted to delineate chr. 1q21-q22 for affected gene(s) in hepatocellular carcinoma (HCC) by array-CGH and detected copy number gains of ρ-guanine nucleotide exchange factor-H1 (GEF-H1) as most significant event. Gene expression evaluation in the HCC cohort indicated common up-regulations of GEF-H1 in 64% tumours compared to adjacent non-tumoural liver (64/100; paired t-test p < 0.0001). Moreover, GEF-H1 over-expressions correlated with microvascular invasion and advanced-stage tumours (p < 0.05). High GEF-H1 levels also predict shorter disease-free and overall survival of HCC patients (p < 0.03). Functional knock-down of GEF-H1 by RNAi indicated marked reduction in cell invasion through matrigel and an inhibition of cell migration (p < 0.035), but an effect on cell viability was not apparent. More interestingly, a mesenchymal-epithelial transition (MET) was readily observed in GEF-H1 knock-down cells, where a concomitant re-expression of epithelial markers (E-cadherin and cytokeratin 18) and cell adhesion proteins (α-catenin and γ-catenin) was found but down-regulation of mesenchymal features (N-cadherin, vimentin and fibronectin). This phenotype was accompanied by reduced filamentous actin polymerizations and diminution of the stress fibre formation. In addition, reduced active form of GTP-RhoA, together with its downstream effectors, including cleaved ROCK1 and phosphorylated MLC2, were also detected in GEF-H1-depleted cells. Taken together, our findings underscore a potent oncogenic role for GEF-H1 in promoting the metastatic potentials of HCC, possibly through activation of RhoA signalling and the EMT phenomenon.

Keywords: EMT; GEF-H1; RhoA; hepatocellular carcinoma; oncogene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Carcinoma, Hepatocellular* / genetics
  • Carcinoma, Hepatocellular* / metabolism
  • Carcinoma, Hepatocellular* / secondary
  • Cell Movement / genetics
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Epithelial-Mesenchymal Transition / physiology
  • Female
  • Humans
  • Liver Neoplasms* / genetics
  • Liver Neoplasms* / metabolism
  • Liver Neoplasms* / pathology
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Phenotype
  • RNA, Small Interfering / genetics
  • Rho Guanine Nucleotide Exchange Factors / genetics*
  • Rho Guanine Nucleotide Exchange Factors / metabolism
  • Signal Transduction / physiology*
  • rhoA GTP-Binding Protein / metabolism*


  • ARHGEF2 protein, human
  • RNA, Small Interfering
  • Rho Guanine Nucleotide Exchange Factors
  • RHOA protein, human
  • rhoA GTP-Binding Protein