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Article: Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion
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TitleClinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion
 
AuthorsChen, L1 2
Yuan, YF1
Li, Y1
Chan, THM2
Zheng, BJ2
Huang, J1
Guan, XY1 2
 
KeywordsMedical sciences
Gastroenterology
 
Issue Date2011
 
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
 
CitationGut, 2011, v. 60 n. 4, p. 534-543 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gut.2010.224071
 
AbstractBackground: Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. It is difficult to detect early, has a high recurrence rate and is refractory to chemotherapies. Amplification of 1q21 is one of the most frequent genetic alterations in HCC. CHD1L is a newly identified oncogene responsible for 1q21 amplification. This study aims to investigate the role of CHD1L in predicting prognosis and chemotherapy response of patients with HCC, its chemoresistant mechanism and whether virus-mediated CHD1L silencing has therapeutic potentials for HCC treatment. Methods: The clinical significance of CHD1L in a cohort of 109 HCC cases including 50 cases who received transarterial chemoembolisation treatment was assessed by clinical correlation and Kaplan-Meier analyses. A CHD1L-overexpressing cell model was generated and the mechanism of chemoresistance involving CHD1L was investigated. An adenovirus-mediated silencing method was used to knockdown CHD1L, and its effects on tumorigenicity and chemoresistance were investigated in vivo and in vitro. Results: Overexpression of CHD1L was significantly associated with tumour microsatellite formation (p=0.045), advanced tumour stage (p=0.018), overall survival time (p=0.002), overall survival time of patients who received transarterial chemoembolisation treatment (p=0.028) and chemoresistance (p=0.020) in HCC. Interestingly, CHD1L could inhibit apoptosis induced by 5-fluorourail (5-FU) but not doxorubicin. The mechanistic study revealed that the involvement of the Nur77-mediated pathway in chemotherapeutic agent-induced apoptosis can dictate if CHD1L could confer resistance to chemotherapy. Furthermore, an adenoviral vector containing short hairpin RNAs against CHD1L (CHD1L-shRNAs) could suppress cell growth, clonogenicity and chemoresistance to 5-FU. An in vivo study found that CHD1L-shRNAs could inhibit xenograft tumour growth and increase the sensitivity of tumour cells to 5-FU in nude mice. Conclusions: This study highlighted for the first time the prognostic value of CHD1L in HCC and the potential application of virus-mediated CHD1L silencing in HCC treatment.
 
ISSN0017-5749
2012 Impact Factor: 10.732
2012 SCImago Journal Rankings: 3.379
 
DOIhttp://dx.doi.org/10.1136/gut.2010.224071
 
ISI Accession Number IDWOS:000288010600019
Funding AgencyGrant Number
Hong Kong Research Grant CouncilHKU 7656/07M
HKU5/CRF/08
HKU 7/CRG09
Sun Yat-Sen University85000-3171311
National Natural Science Foundation of China30772475
National Key Sci-Tech Special Project of Infectious Diseases2008ZX10002-022
Funding Information:

This work was supported by a Hong Kong Research Grant Council Grant (HKU 7656/07M), Hong Kong RGC Collaborative Research Grants (HKU5/CRF/08 and HKU 7/CRG09), the 'Hundred Talents Program' at Sun Yat-Sen University (85000-3171311) and grants from the National Natural Science Foundation of China (30772475) and the National Key Sci-Tech Special Project of Infectious Diseases (Grant 2008ZX10002-022).

 
ReferencesReferences in Scopus
 
GrantsLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury
 
DC FieldValue
dc.contributor.authorChen, L
 
dc.contributor.authorYuan, YF
 
dc.contributor.authorLi, Y
 
dc.contributor.authorChan, THM
 
dc.contributor.authorZheng, BJ
 
dc.contributor.authorHuang, J
 
dc.contributor.authorGuan, XY
 
dc.date.accessioned2011-07-27T01:31:18Z
 
dc.date.available2011-07-27T01:31:18Z
 
dc.date.issued2011
 
dc.description.abstractBackground: Hepatocellular carcinoma (HCC) is among the most lethal of human malignancies. It is difficult to detect early, has a high recurrence rate and is refractory to chemotherapies. Amplification of 1q21 is one of the most frequent genetic alterations in HCC. CHD1L is a newly identified oncogene responsible for 1q21 amplification. This study aims to investigate the role of CHD1L in predicting prognosis and chemotherapy response of patients with HCC, its chemoresistant mechanism and whether virus-mediated CHD1L silencing has therapeutic potentials for HCC treatment. Methods: The clinical significance of CHD1L in a cohort of 109 HCC cases including 50 cases who received transarterial chemoembolisation treatment was assessed by clinical correlation and Kaplan-Meier analyses. A CHD1L-overexpressing cell model was generated and the mechanism of chemoresistance involving CHD1L was investigated. An adenovirus-mediated silencing method was used to knockdown CHD1L, and its effects on tumorigenicity and chemoresistance were investigated in vivo and in vitro. Results: Overexpression of CHD1L was significantly associated with tumour microsatellite formation (p=0.045), advanced tumour stage (p=0.018), overall survival time (p=0.002), overall survival time of patients who received transarterial chemoembolisation treatment (p=0.028) and chemoresistance (p=0.020) in HCC. Interestingly, CHD1L could inhibit apoptosis induced by 5-fluorourail (5-FU) but not doxorubicin. The mechanistic study revealed that the involvement of the Nur77-mediated pathway in chemotherapeutic agent-induced apoptosis can dictate if CHD1L could confer resistance to chemotherapy. Furthermore, an adenoviral vector containing short hairpin RNAs against CHD1L (CHD1L-shRNAs) could suppress cell growth, clonogenicity and chemoresistance to 5-FU. An in vivo study found that CHD1L-shRNAs could inhibit xenograft tumour growth and increase the sensitivity of tumour cells to 5-FU in nude mice. Conclusions: This study highlighted for the first time the prognostic value of CHD1L in HCC and the potential application of virus-mediated CHD1L silencing in HCC treatment.
 
dc.description.naturepublished_or_final_version
 
dc.identifier.citationGut, 2011, v. 60 n. 4, p. 534-543 [How to Cite?]
DOI: http://dx.doi.org/10.1136/gut.2010.224071
 
dc.identifier.doihttp://dx.doi.org/10.1136/gut.2010.224071
 
dc.identifier.epage543
 
dc.identifier.hkuros188643
 
dc.identifier.isiWOS:000288010600019
Funding AgencyGrant Number
Hong Kong Research Grant CouncilHKU 7656/07M
HKU5/CRF/08
HKU 7/CRG09
Sun Yat-Sen University85000-3171311
National Natural Science Foundation of China30772475
National Key Sci-Tech Special Project of Infectious Diseases2008ZX10002-022
Funding Information:

This work was supported by a Hong Kong Research Grant Council Grant (HKU 7656/07M), Hong Kong RGC Collaborative Research Grants (HKU5/CRF/08 and HKU 7/CRG09), the 'Hundred Talents Program' at Sun Yat-Sen University (85000-3171311) and grants from the National Natural Science Foundation of China (30772475) and the National Key Sci-Tech Special Project of Infectious Diseases (Grant 2008ZX10002-022).

 
dc.identifier.issn0017-5749
2012 Impact Factor: 10.732
2012 SCImago Journal Rankings: 3.379
 
dc.identifier.issue4
 
dc.identifier.openurl
 
dc.identifier.pmid21068133
 
dc.identifier.scopuseid_2-s2.0-79952532633
 
dc.identifier.spage534
 
dc.identifier.urihttp://hdl.handle.net/10722/135283
 
dc.identifier.volume60
 
dc.languageeng
 
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
 
dc.publisher.placeUnited Kingdom
 
dc.relation.ispartofGut
 
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury
 
dc.relation.referencesReferences in Scopus
 
dc.rightsGut. Copyright © B M J Publishing Group.
 
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License
 
dc.subject.meshAdenoviridae - genetics
 
dc.subject.meshAdult
 
dc.subject.meshAged
 
dc.subject.meshAnimals
 
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols - therapeutic use
 
dc.subject.meshApoptosis - drug effects
 
dc.subject.meshCarcinoma, Hepatocellular - drug therapy - metabolism
 
dc.subject.meshDNA Helicases - genetics - metabolism - physiology
 
dc.subject.meshDNA-Binding Proteins - genetics - metabolism - physiology
 
dc.subject.meshDoxorubicin - pharmacology
 
dc.subject.meshDrug Resistance, Neoplasm
 
dc.subject.meshFemale
 
dc.subject.meshFluorouracil - pharmacology - therapeutic use
 
dc.subject.meshGene Silencing
 
dc.subject.meshGene Therapy - methods
 
dc.subject.meshGenetic Vectors
 
dc.subject.meshHumans
 
dc.subject.meshLiver Neoplasms - drug therapy - metabolism
 
dc.subject.meshMale
 
dc.subject.meshMice
 
dc.subject.meshMice, Nude
 
dc.subject.meshMiddle Aged
 
dc.subject.meshNeoplasm Proteins - genetics - metabolism - physiology
 
dc.subject.meshPrognosis
 
dc.subject.meshRetrospective Studies
 
dc.subject.meshSignal Transduction
 
dc.subject.meshTreatment Outcome
 
dc.subject.meshTumor Cells, Cultured
 
dc.subject.meshTumor Markers, Biological - metabolism
 
dc.subject.meshXenograft Model Antitumor Assays
 
dc.subject.meshYoung Adult
 
dc.subjectMedical sciences
 
dc.subjectGastroenterology
 
dc.titleClinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion
 
dc.typeArticle
 
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Author Affiliations
  1. Sun Yat-Sen University Cancer Center
  2. The University of Hong Kong