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
2011 Impact Factor: 10.111
2011 SCImago Journal Rankings: 0.883
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 Field
Value
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.grantLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury
dc.description.grantcode99532
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
2011 Impact Factor: 10.111
2011 SCImago Journal Rankings: 0.883
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.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
Author Affiliations
  1. Sun Yat-Sen University Cancer Center
  2. The University of Hong Kong