title: GEF-H1 over-expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signalling.
abstract: 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.
authors: Department of Anatomical and Cellular Pathology, Li Ka-Shing Institute of Health Sciences, Chinese University of Hong Kong, Shatin, Hong Kong, People's Republic of China; Department of Nutrition and Food Management, HKU SPACE Po Leung Kuk Community College, Hong Kong, People's Republic of China.
authors: Ibis K C
authors: IK
authors: Cheng
authors: Bruce C K
authors: BC
authors: Tsang
authors: Keng Po
authors: KP
authors: Lai
authors: Arthur K K
authors: AK
authors: Ching
authors: Anthony W H
authors: AW
authors: Chan
authors: Ka-Fai
authors: KF
authors: To
authors: Paul B S
authors: PB
authors: Lai
authors: Nathalie
authors: N
authors: Wong
mesh_terms: D000328:Adult; D000368:Aged; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000378:metabolism / Q000556:secondary; D002465:Cell Movement / Q000235:genetics; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics; D064067:Rho Guanine Nucleotide Exchange Factors / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C577356:ARHGEF2 protein, human; D034741:RNA, Small Interfering; D064067:Rho Guanine Nucleotide Exchange Factors; C066737:RHOA protein, human; D020742:rhoA GTP-Binding Protein