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Article: CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients
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TitleCHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients
 
AuthorsChen, L2
Chan, THM2
Yuan, YF1
Hu, L2
Huang, J1
Ma, S2
Wang, J2
Dong, SS2
Tang, KH2
Xie, D1
Li, Y1
Guan, XY2 1
 
Issue Date2010
 
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
CitationJournal Of Clinical Investigation, 2010, v. 120 n. 4, p. 1178-1191 [How to Cite?]
DOI: http://dx.doi.org/10.1172/JCI40665
 
AbstractChromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified oncogene localized at 1q21, a frequently amplified region in hepatocellular carcinoma (HCC). To explore its oncogenic mechanisms, we set out to identify CHD1L-regulated genes using a chromatin immunoprecipitation-based (ChIP-based) cloning strategy in a human HCC cell line. We then further characterized 1 identified gene, ARHGEF9, which encodes a specific guanine nucleotide exchange factor (GEF) for the Rho small GTPase Cdc42. Overexpression of ARHGEF9 was detected in approximately half the human HCC samples analyzed and positively correlated with CHD1L overexpression. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition (EMT) via ARHGEF9-mediated Cdc42 activation. Silencing ARHGEF9 expression by RNAi effectively abolished the invasive and metastatic abilities of CHD1L in mice. Furthermore, investigation of clinical HCC specimens showed that CHD1L and ARHGEF9 were markedly overexpressed in metastatic HCC tissue compared with healthy tissue. Increased expression of CHD1L was often observed at the invasive front of HCC tumors and correlated with venous infiltration, microsatellite tumor nodule formation, and poor disease-free survival. These findings suggest that CHD1L-ARHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis.
 
ISSN0021-9738
2012 Impact Factor: 12.812
2012 SCImago Journal Rankings: 7.246
 
DOIhttp://dx.doi.org/10.1172/JCI40665
 
PubMed Central IDPMC2846051
 
ISI Accession Number IDWOS:000276258100028
Funding AgencyGrant Number
Hong Kong Research Grant CouncilHKU 7656/07M
HKU 1/06C
HKU5/CRF/08
Sun Yat-sen University85000-3171311
Major State Basic Research Program of China2006CB910104
National Natural Science Foundation of China30772475
Funding Information:

This work was supported by a Hong Kong Research Grant Council Grant (HKU 7656/07M), Hong Kong Research Grant Council Central Allocations (HKU 1/06C and HKU5/CRF/08), the "Hundred Talents Program" at Sun Yat-sen University (85000-3171311), the Major State Basic Research Program of China (2006CB910104), and a grant from the National Natural Science Foundation of China (30772475).

 
ReferencesReferences in Scopus
 
GrantsMolecular pathology of liver cancer - a multidisciplinary study
Liver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury
 
DC FieldValue
dc.contributor.authorChen, L
 
dc.contributor.authorChan, THM
 
dc.contributor.authorYuan, YF
 
dc.contributor.authorHu, L
 
dc.contributor.authorHuang, J
 
dc.contributor.authorMa, S
 
dc.contributor.authorWang, J
 
dc.contributor.authorDong, SS
 
dc.contributor.authorTang, KH
 
dc.contributor.authorXie, D
 
dc.contributor.authorLi, Y
 
dc.contributor.authorGuan, XY
 
dc.date.accessioned2010-09-06T06:36:25Z
 
dc.date.available2010-09-06T06:36:25Z
 
dc.date.issued2010
 
dc.description.abstractChromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) is a recently identified oncogene localized at 1q21, a frequently amplified region in hepatocellular carcinoma (HCC). To explore its oncogenic mechanisms, we set out to identify CHD1L-regulated genes using a chromatin immunoprecipitation-based (ChIP-based) cloning strategy in a human HCC cell line. We then further characterized 1 identified gene, ARHGEF9, which encodes a specific guanine nucleotide exchange factor (GEF) for the Rho small GTPase Cdc42. Overexpression of ARHGEF9 was detected in approximately half the human HCC samples analyzed and positively correlated with CHD1L overexpression. In vitro and in vivo functional studies in mice showed that CHD1L contributed to tumor cell migration, invasion, and metastasis by increasing cell motility and inducing filopodia formation and epithelial-mesenchymal transition (EMT) via ARHGEF9-mediated Cdc42 activation. Silencing ARHGEF9 expression by RNAi effectively abolished the invasive and metastatic abilities of CHD1L in mice. Furthermore, investigation of clinical HCC specimens showed that CHD1L and ARHGEF9 were markedly overexpressed in metastatic HCC tissue compared with healthy tissue. Increased expression of CHD1L was often observed at the invasive front of HCC tumors and correlated with venous infiltration, microsatellite tumor nodule formation, and poor disease-free survival. These findings suggest that CHD1L-ARHGEF9-Cdc42-EMT might be a novel pathway involved in HCC progression and metastasis.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationJournal Of Clinical Investigation, 2010, v. 120 n. 4, p. 1178-1191 [How to Cite?]
DOI: http://dx.doi.org/10.1172/JCI40665
 
dc.identifier.doihttp://dx.doi.org/10.1172/JCI40665
 
dc.identifier.eissn1558-8238
 
dc.identifier.epage1191
 
dc.identifier.hkuros169645
 
dc.identifier.isiWOS:000276258100028
Funding AgencyGrant Number
Hong Kong Research Grant CouncilHKU 7656/07M
HKU 1/06C
HKU5/CRF/08
Sun Yat-sen University85000-3171311
Major State Basic Research Program of China2006CB910104
National Natural Science Foundation of China30772475
Funding Information:

This work was supported by a Hong Kong Research Grant Council Grant (HKU 7656/07M), Hong Kong Research Grant Council Central Allocations (HKU 1/06C and HKU5/CRF/08), the "Hundred Talents Program" at Sun Yat-sen University (85000-3171311), the Major State Basic Research Program of China (2006CB910104), and a grant from the National Natural Science Foundation of China (30772475).

 
dc.identifier.issn0021-9738
2012 Impact Factor: 12.812
2012 SCImago Journal Rankings: 7.246
 
dc.identifier.issue4
 
dc.identifier.openurl
 
dc.identifier.pmcidPMC2846051
 
dc.identifier.pmid20335658
 
dc.identifier.scopuseid_2-s2.0-77951176116
 
dc.identifier.spage1178
 
dc.identifier.urihttp://hdl.handle.net/10722/71912
 
dc.identifier.volume120
 
dc.languageeng
 
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
 
dc.publisher.placeUnited States
 
dc.relation.ispartofJournal of Clinical Investigation
 
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study
 
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury
 
dc.relation.referencesReferences in Scopus
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshAnimals
 
dc.subject.meshCarcinoma, Hepatocellular - etiology - pathology
 
dc.subject.meshDNA Helicases - physiology
 
dc.subject.meshDNA-Binding Proteins - physiology
 
dc.subject.meshLiver Neoplasms - etiology - pathology
 
dc.titleCHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients
 
dc.typeArticle
 
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Author Affiliations
  1. Sun Yat-Sen University Cancer Center
  2. The University of Hong Kong