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Article: CHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients

TitleCHD1L promotes hepatocellular carcinoma progression and metastasis in mice and is associated with these processes in human patients
Authors
Issue Date2010
PublisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.org
Citation
Journal Of Clinical Investigation, 2010, v. 120 n. 4, p. 1178-1191 How to Cite?
Abstract
Chromodomain 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.
Persistent Identifierhttp://hdl.handle.net/10722/71912
ISSN
2013 Impact Factor: 13.765
2013 SCImago Journal Rankings: 9.511
PubMed Central ID
ISI Accession Number ID
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).

References
Grants

 

Author Affiliations
  1. Sun Yat-Sen University Cancer Center
  2. The University of Hong Kong
DC FieldValueLanguage
dc.contributor.authorChen, Len_HK
dc.contributor.authorChan, THMen_HK
dc.contributor.authorYuan, YFen_HK
dc.contributor.authorHu, Len_HK
dc.contributor.authorHuang, Jen_HK
dc.contributor.authorMa, Sen_HK
dc.contributor.authorWang, Jen_HK
dc.contributor.authorDong, SSen_HK
dc.contributor.authorTang, KHen_HK
dc.contributor.authorXie, Den_HK
dc.contributor.authorLi, Yen_HK
dc.contributor.authorGuan, XYen_HK
dc.date.accessioned2010-09-06T06:36:25Z-
dc.date.available2010-09-06T06:36:25Z-
dc.date.issued2010en_HK
dc.identifier.citationJournal Of Clinical Investigation, 2010, v. 120 n. 4, p. 1178-1191en_HK
dc.identifier.issn0021-9738en_HK
dc.identifier.urihttp://hdl.handle.net/10722/71912-
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.en_HK
dc.languageengen_HK
dc.publisherAmerican Society for Clinical Investigation. The Journal's web site is located at http://www.jci.orgen_HK
dc.relation.ispartofJournal of Clinical Investigationen_HK
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 patientsen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0021-9738&volume=120&issue=4&spage=1178&epage=1191&date=2010&atitle=CHD1L+promotes+hepatocellular+carcinoma+progression+and+metastasis+in+mice+and+is+associated+with+these+processes+in+human+patientsen_HK
dc.identifier.emailMa, S:sma@pathology.hku.hken_HK
dc.identifier.emailGuan, XY:xyguan@hkucc.hku.hken_HK
dc.identifier.authorityMa, S=rp00506en_HK
dc.identifier.authorityGuan, XY=rp00454en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1172/JCI40665en_HK
dc.identifier.pmid20335658en_HK
dc.identifier.pmcidPMC2846051-
dc.identifier.scopuseid_2-s2.0-77951176116en_HK
dc.identifier.hkuros169645en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-77951176116&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume120en_HK
dc.identifier.issue4en_HK
dc.identifier.spage1178en_HK
dc.identifier.epage1191en_HK
dc.identifier.eissn1558-8238-
dc.identifier.isiWOS:000276258100028-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury-
dc.identifier.scopusauthoridChen, L=23569135400en_HK
dc.identifier.scopusauthoridChan, THM=26431726400en_HK
dc.identifier.scopusauthoridYuan, YF=7402708979en_HK
dc.identifier.scopusauthoridHu, L=34770075600en_HK
dc.identifier.scopusauthoridHuang, J=24467982900en_HK
dc.identifier.scopusauthoridMa, S=16444895800en_HK
dc.identifier.scopusauthoridWang, J=24371445200en_HK
dc.identifier.scopusauthoridDong, SS=35788109500en_HK
dc.identifier.scopusauthoridTang, KH=24781597200en_HK
dc.identifier.scopusauthoridXie, D=35070710200en_HK
dc.identifier.scopusauthoridLi, Y=36078824800en_HK
dc.identifier.scopusauthoridGuan, XY=7201463221en_HK

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