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Article: Clinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion

TitleClinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletion
Authors
KeywordsMedical sciences
Gastroenterology
Issue Date2011
PublisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/
Citation
Gut, 2011, v. 60 n. 4, p. 534-543 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/135283
ISSN
2015 Impact Factor: 14.921
2015 SCImago Journal Rankings: 6.474
ISI Accession Number ID
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).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorChen, Len_HK
dc.contributor.authorYuan, YFen_HK
dc.contributor.authorLi, Yen_HK
dc.contributor.authorChan, THMen_HK
dc.contributor.authorZheng, BJen_HK
dc.contributor.authorHuang, Jen_HK
dc.contributor.authorGuan, XYen_HK
dc.date.accessioned2011-07-27T01:31:18Z-
dc.date.available2011-07-27T01:31:18Z-
dc.date.issued2011en_HK
dc.identifier.citationGut, 2011, v. 60 n. 4, p. 534-543en_HK
dc.identifier.issn0017-5749en_HK
dc.identifier.urihttp://hdl.handle.net/10722/135283-
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.en_HK
dc.languageengen_US
dc.publisherBMJ Publishing Group. The Journal's web site is located at http://gut.bmjjournals.com/en_HK
dc.relation.ispartofGuten_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsGut. Copyright © B M J Publishing Group.-
dc.subjectMedical sciences-
dc.subjectGastroenterology-
dc.subject.meshAdenoviridae - geneticsen_HK
dc.subject.meshAdulten_HK
dc.subject.meshAgeden_HK
dc.subject.meshAnimalsen_HK
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols - therapeutic useen_HK
dc.subject.meshApoptosis - drug effectsen_HK
dc.subject.meshCarcinoma, Hepatocellular - drug therapy - metabolismen_HK
dc.subject.meshDNA Helicases - genetics - metabolism - physiologyen_HK
dc.subject.meshDNA-Binding Proteins - genetics - metabolism - physiologyen_HK
dc.subject.meshDoxorubicin - pharmacologyen_HK
dc.subject.meshDrug Resistance, Neoplasmen_HK
dc.subject.meshFemaleen_HK
dc.subject.meshFluorouracil - pharmacology - therapeutic useen_HK
dc.subject.meshGene Silencingen_HK
dc.subject.meshGene Therapy - methodsen_HK
dc.subject.meshGenetic Vectorsen_HK
dc.subject.meshHumansen_HK
dc.subject.meshLiver Neoplasms - drug therapy - metabolismen_HK
dc.subject.meshMaleen_HK
dc.subject.meshMiceen_HK
dc.subject.meshMice, Nudeen_HK
dc.subject.meshMiddle Ageden_HK
dc.subject.meshNeoplasm Proteins - genetics - metabolism - physiologyen_HK
dc.subject.meshPrognosisen_HK
dc.subject.meshRetrospective Studiesen_HK
dc.subject.meshSignal Transductionen_HK
dc.subject.meshTreatment Outcomeen_HK
dc.subject.meshTumor Cells, Cultureden_HK
dc.subject.meshTumor Markers, Biological - metabolismen_HK
dc.subject.meshXenograft Model Antitumor Assaysen_HK
dc.subject.meshYoung Adulten_HK
dc.titleClinical significance of CHD1L in hepatocellular carcinoma and therapeutic potentials of virus-mediated CHD1L depletionen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0017-5749&volume=60&issue=4&spage=534&epage=543&date=2010&atitle=Clinical+significance+of+CHD1L+in+hepatocellular+carcinoma+and+therapeutic+potentials+of+virus-mediated+CHD1L+depletion-
dc.identifier.emailZheng, BJ:bzheng@hkucc.hku.hken_HK
dc.identifier.emailGuan, XY:xyguan@hkucc.hku.hken_HK
dc.identifier.authorityZheng, BJ=rp00353en_HK
dc.identifier.authorityGuan, XY=rp00454en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1136/gut.2010.224071en_HK
dc.identifier.pmid21068133-
dc.identifier.scopuseid_2-s2.0-79952532633en_HK
dc.identifier.hkuros188643en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79952532633&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume60en_HK
dc.identifier.issue4en_HK
dc.identifier.spage534en_HK
dc.identifier.epage543en_HK
dc.identifier.isiWOS:000288010600019-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury-
dc.identifier.scopusauthoridChen, L=23569135400en_HK
dc.identifier.scopusauthoridYuan, YF=7402708979en_HK
dc.identifier.scopusauthoridLi, Y=36078636500en_HK
dc.identifier.scopusauthoridChan, THM=26431726400en_HK
dc.identifier.scopusauthoridZheng, BJ=7201780588en_HK
dc.identifier.scopusauthoridHuang, J=36070752600en_HK
dc.identifier.scopusauthoridGuan, XY=7201463221en_HK

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