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GEF‐H1 over‐expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signalling
Author(s) -
Cheng Ibis KC,
Tsang Bruce CK,
Lai Keng Po,
Ching Arthur KK,
Chan Anthony WH,
To KaFai,
Lai Paul BS,
Wong Nathalie
Publication year - 2012
Publication title -
the journal of pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.964
H-Index - 184
eISSN - 1096-9896
pISSN - 0022-3417
DOI - 10.1002/path.4084
Subject(s) - rhoa , guanine nucleotide exchange factor , cancer research , rock1 , biology , vimentin , microbiology and biotechnology , gtpase , signal transduction , immunology , immunohistochemistry
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. Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.