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

TitleGEF-H1 over-expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signalling
Authors
KeywordsEmt
Gef-H1
Hepatocellular Carcinoma
Oncogene
Rhoa
Issue Date2012
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal Of Pathology, 2012, v. 228 n. 4, p. 575-585 How to Cite?
AbstractThe 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 θ-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 (a-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.
Persistent Identifierhttp://hdl.handle.net/10722/183404
ISSN
2015 Impact Factor: 7.381
2015 SCImago Journal Rankings: 4.176
ISI Accession Number ID
References

 

DC FieldValueLanguage
dc.contributor.authorCheng, IKCen_US
dc.contributor.authorTsang, BCKen_US
dc.contributor.authorLai, KPen_US
dc.contributor.authorChing, AKKen_US
dc.contributor.authorChan, AWHen_US
dc.contributor.authorTo, KFen_US
dc.contributor.authorLai, PBSen_US
dc.contributor.authorWong, Nen_US
dc.date.accessioned2013-05-27T07:12:40Z-
dc.date.available2013-05-27T07:12:40Z-
dc.date.issued2012en_US
dc.identifier.citationJournal Of Pathology, 2012, v. 228 n. 4, p. 575-585en_US
dc.identifier.issn0022-3417en_US
dc.identifier.urihttp://hdl.handle.net/10722/183404-
dc.description.abstractThe 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 θ-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 (a-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.en_US
dc.languageengen_US
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130en_US
dc.relation.ispartofJournal of Pathologyen_US
dc.subjectEmten_US
dc.subjectGef-H1en_US
dc.subjectHepatocellular Carcinomaen_US
dc.subjectOncogeneen_US
dc.subjectRhoaen_US
dc.titleGEF-H1 over-expression in hepatocellular carcinoma promotes cell motility via activation of RhoA signallingen_US
dc.typeArticleen_US
dc.identifier.emailLai, KP: ballllai@hotmail.comen_US
dc.identifier.authorityLai, KP=rp01753en_US
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/path.4084en_US
dc.identifier.pmid22847784-
dc.identifier.scopuseid_2-s2.0-84871237402en_US
dc.identifier.hkuros223753-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84871237402&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume228en_US
dc.identifier.issue4en_US
dc.identifier.spage575en_US
dc.identifier.epage585en_US
dc.identifier.isiWOS:000313949800015-
dc.publisher.placeUnited Kingdomen_US
dc.identifier.scopusauthoridCheng, IKC=35783881300en_US
dc.identifier.scopusauthoridTsang, BCK=55531509400en_US
dc.identifier.scopusauthoridLai, KP=7402135707en_US
dc.identifier.scopusauthoridChing, AKK=35083263600en_US
dc.identifier.scopusauthoridChan, AWH=55322037300en_US
dc.identifier.scopusauthoridTo, KF=7101911940en_US
dc.identifier.scopusauthoridLai, PBS=7202946421en_US
dc.identifier.scopusauthoridWong, N=7202836653en_US

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