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Article: Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
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TitleTranslationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
 
AuthorsChan, THM2
Chen, L2
Liu, M2
Hu, L2
Zheng, BJ2
Poon, VKM2
Huang, P1
Yuan, YF1
Huang, JD2
Yang, J2
Tsao, GSW2
Guan, XY2 1
 
Issue Date2012
 
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
 
CitationHepatology, 2012, v. 55 n. 2, p. 491-505 [How to Cite?]
DOI: http://dx.doi.org/10.1002/hep.24709
 
AbstractEmerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC). To better understand the molecular mechanisms underlying HCC cases carrying CHD1L amplification (>50% HCCs), we identified a CHD1L target, translationally controlled tumor protein (TCTP), and investigated its role in HCC progression. Here, we report that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activates TCTP transcription. Overexpression of TCTP was detected in 40.7% of human HCC samples analyzed and positively correlated with CHD1L overexpression. Clinically, overexpression of TCTP was significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034). In multivariate analyses, TCTP was determined to be an independent marker associated with poor prognostic outcomes. In vitro and in vivo functional studies in mice showed that TCTP has tumorigenic abilities, and overexpression of TCTP induced by CHD1L contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25C during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr15 and decreased Cdk1 activity. As a consequence, the sudden drop of Cdk1 activity in mitosis induced a faster mitotic exit and chromosome missegregation, which led to chromosomal instability. The depletion experiment proved that the tumorigenicity of TCTP was linked to its role in mitotic defects. Conclusion: Collectively, we reveal a novel molecular pathway (CHD1L/TCTP/Cdc25C/Cdk1), which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy. © 2011 American Association for the Study of Liver Diseases.
 
ISSN0270-9139
2012 Impact Factor: 12.003
2012 SCImago Journal Rankings: 4.260
 
DOIhttp://dx.doi.org/10.1002/hep.24709
 
ISI Accession Number IDWOS:000299632900018
Funding AgencyGrant Number
Hong Kong Research Grant CouncilHKU 7656/07M
Hong Kong Research Grant Council Central AllocationHKU5/CRF/08
Hong Kong RGCHKU 7/CRG09
Sun Yat-Sen University850003171311
Major State Basic Research Program of China2006CB910104
National Natural Science Foundation of China30772475
30971606
Funding Information:

This work was supported by a Hong Kong Research Grant Council Grant (HKU 7656/07M), a Hong Kong Research Grant Council Central Allocation (HKU5/CRF/08), a Hong Kong RGC Collaborative Research Grant (HKU 7/CRG09), the "Hundred Talents Program" at Sun Yat-Sen University (850003171311), the Major State Basic Research Program of China (2006CB910104), and grants from the National Natural Science Foundation of China (30772475 and 30971606).

 
ReferencesReferences in Scopus
 
GrantsLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury
 
DC FieldValue
dc.contributor.authorChan, THM
 
dc.contributor.authorChen, L
 
dc.contributor.authorLiu, M
 
dc.contributor.authorHu, L
 
dc.contributor.authorZheng, BJ
 
dc.contributor.authorPoon, VKM
 
dc.contributor.authorHuang, P
 
dc.contributor.authorYuan, YF
 
dc.contributor.authorHuang, JD
 
dc.contributor.authorYang, J
 
dc.contributor.authorTsao, GSW
 
dc.contributor.authorGuan, XY
 
dc.date.accessioned2012-06-26T06:12:25Z
 
dc.date.available2012-06-26T06:12:25Z
 
dc.date.issued2012
 
dc.description.abstractEmerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC). To better understand the molecular mechanisms underlying HCC cases carrying CHD1L amplification (>50% HCCs), we identified a CHD1L target, translationally controlled tumor protein (TCTP), and investigated its role in HCC progression. Here, we report that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activates TCTP transcription. Overexpression of TCTP was detected in 40.7% of human HCC samples analyzed and positively correlated with CHD1L overexpression. Clinically, overexpression of TCTP was significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034). In multivariate analyses, TCTP was determined to be an independent marker associated with poor prognostic outcomes. In vitro and in vivo functional studies in mice showed that TCTP has tumorigenic abilities, and overexpression of TCTP induced by CHD1L contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25C during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr15 and decreased Cdk1 activity. As a consequence, the sudden drop of Cdk1 activity in mitosis induced a faster mitotic exit and chromosome missegregation, which led to chromosomal instability. The depletion experiment proved that the tumorigenicity of TCTP was linked to its role in mitotic defects. Conclusion: Collectively, we reveal a novel molecular pathway (CHD1L/TCTP/Cdc25C/Cdk1), which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy. © 2011 American Association for the Study of Liver Diseases.
 
dc.description.natureLink_to_OA_fulltext
 
dc.identifier.citationHepatology, 2012, v. 55 n. 2, p. 491-505 [How to Cite?]
DOI: http://dx.doi.org/10.1002/hep.24709
 
dc.identifier.doihttp://dx.doi.org/10.1002/hep.24709
 
dc.identifier.eissn1527-3350
 
dc.identifier.epage505
 
dc.identifier.hkuros203479
 
dc.identifier.isiWOS:000299632900018
Funding AgencyGrant Number
Hong Kong Research Grant CouncilHKU 7656/07M
Hong Kong Research Grant Council Central AllocationHKU5/CRF/08
Hong Kong RGCHKU 7/CRG09
Sun Yat-Sen University850003171311
Major State Basic Research Program of China2006CB910104
National Natural Science Foundation of China30772475
30971606
Funding Information:

This work was supported by a Hong Kong Research Grant Council Grant (HKU 7656/07M), a Hong Kong Research Grant Council Central Allocation (HKU5/CRF/08), a Hong Kong RGC Collaborative Research Grant (HKU 7/CRG09), the "Hundred Talents Program" at Sun Yat-Sen University (850003171311), the Major State Basic Research Program of China (2006CB910104), and grants from the National Natural Science Foundation of China (30772475 and 30971606).

 
dc.identifier.issn0270-9139
2012 Impact Factor: 12.003
2012 SCImago Journal Rankings: 4.260
 
dc.identifier.issue2
 
dc.identifier.pmid21953552
 
dc.identifier.scopuseid_2-s2.0-84863011661
 
dc.identifier.spage491
 
dc.identifier.urihttp://hdl.handle.net/10722/150849
 
dc.identifier.volume55
 
dc.languageeng
 
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
 
dc.publisher.placeUnited States
 
dc.relation.ispartofHepatology
 
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury
 
dc.relation.referencesReferences in Scopus
 
dc.subject.meshCdc2 Protein Kinase - Metabolism
 
dc.subject.meshCarcinoma, Hepatocellular - Metabolism
 
dc.subject.meshCell Division
 
dc.subject.meshCell Transformation, Neoplastic
 
dc.subject.meshChromosome Segregation
 
dc.subject.meshDna Helicases - Metabolism
 
dc.subject.meshDna-Binding Proteins - Metabolism
 
dc.subject.meshDisease Progression
 
dc.subject.meshElectrophoresis, Gel, Two-Dimensional
 
dc.subject.meshG2 Phase
 
dc.subject.meshHep G2 Cells
 
dc.subject.meshHumans
 
dc.subject.meshLiver Neoplasms - Metabolism
 
dc.subject.meshTumor Markers, Biological - Metabolism
 
dc.subject.meshUp-Regulation
 
dc.subject.meshCdc25 Phosphatases - Metabolism
 
dc.titleTranslationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
 
dc.typeArticle
 
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<description.abstract>Emerging evidence implicates the chromodomain helicase/ATPase DNA binding protein 1-like gene (CHD1L) as a specific oncogene in human hepatocellular carcinoma (HCC). To better understand the molecular mechanisms underlying HCC cases carrying CHD1L amplification (&gt;50% HCCs), we identified a CHD1L target, translationally controlled tumor protein (TCTP), and investigated its role in HCC progression. Here, we report that CHD1L protein directly binds to the promoter region (nt -733 to -1,027) of TCTP and activates TCTP transcription. Overexpression of TCTP was detected in 40.7% of human HCC samples analyzed and positively correlated with CHD1L overexpression. Clinically, overexpression of TCTP was significantly associated with the advanced tumor stage (P = 0.037) and overall survival time of HCC patients (P = 0.034). In multivariate analyses, TCTP was determined to be an independent marker associated with poor prognostic outcomes. In vitro and in vivo functional studies in mice showed that TCTP has tumorigenic abilities, and overexpression of TCTP induced by CHD1L contributed to the mitotic defects of tumor cells. Further mechanistic studies demonstrated that TCTP promoted the ubiquitin-proteasome degradation of Cdc25C during mitotic progression, which caused the failure in the dephosphorylation of Cdk1 on Tyr15 and decreased Cdk1 activity. As a consequence, the sudden drop of Cdk1 activity in mitosis induced a faster mitotic exit and chromosome missegregation, which led to chromosomal instability. The depletion experiment proved that the tumorigenicity of TCTP was linked to its role in mitotic defects. Conclusion: Collectively, we reveal a novel molecular pathway (CHD1L/TCTP/Cdc25C/Cdk1), which causes the malignant transformation of hepatocytes with the phenotypes of accelerated mitotic progression and the production of aneuploidy. &#169; 2011 American Association for the Study of Liver Diseases.</description.abstract>
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Author Affiliations
  1. Sun Yat-Sen University Cancer Center
  2. The University of Hong Kong