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Article: Translationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development

TitleTranslationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma development
Authors
Issue Date2012
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2012, v. 55 n. 2, p. 491-505 How to Cite?
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.
Persistent Identifierhttp://hdl.handle.net/10722/150849
ISSN
2015 Impact Factor: 11.711
2015 SCImago Journal Rankings: 4.752
ISI Accession Number ID
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).

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorChan, THMen_US
dc.contributor.authorChen, Len_US
dc.contributor.authorLiu, Men_US
dc.contributor.authorHu, Len_US
dc.contributor.authorZheng, BJen_US
dc.contributor.authorPoon, VKMen_US
dc.contributor.authorHuang, Pen_US
dc.contributor.authorYuan, YFen_US
dc.contributor.authorHuang, JDen_US
dc.contributor.authorYang, Jen_US
dc.contributor.authorTsao, GSWen_US
dc.contributor.authorGuan, XYen_US
dc.date.accessioned2012-06-26T06:12:25Z-
dc.date.available2012-06-26T06:12:25Z-
dc.date.issued2012en_US
dc.identifier.citationHepatology, 2012, v. 55 n. 2, p. 491-505en_US
dc.identifier.issn0270-9139en_US
dc.identifier.urihttp://hdl.handle.net/10722/150849-
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.en_US
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/en_US
dc.relation.ispartofHepatologyen_US
dc.subject.meshCdc2 Protein Kinase - Metabolismen_US
dc.subject.meshCarcinoma, Hepatocellular - Metabolismen_US
dc.subject.meshCell Divisionen_US
dc.subject.meshCell Transformation, Neoplasticen_US
dc.subject.meshChromosome Segregationen_US
dc.subject.meshDna Helicases - Metabolismen_US
dc.subject.meshDna-Binding Proteins - Metabolismen_US
dc.subject.meshDisease Progressionen_US
dc.subject.meshElectrophoresis, Gel, Two-Dimensionalen_US
dc.subject.meshG2 Phaseen_US
dc.subject.meshHep G2 Cellsen_US
dc.subject.meshHumansen_US
dc.subject.meshLiver Neoplasms - Metabolismen_US
dc.subject.meshTumor Markers, Biological - Metabolismen_US
dc.subject.meshUp-Regulationen_US
dc.subject.meshCdc25 Phosphatases - Metabolismen_US
dc.titleTranslationally controlled tumor protein induces mitotic defects and chromosome missegregation in hepatocellular carcinoma developmenten_US
dc.typeArticleen_US
dc.identifier.emailGuan, XY:xyguan@hkucc.hku.hken_US
dc.identifier.authorityGuan, XY=rp00454en_US
dc.description.naturelink_to_OA_fulltexten_US
dc.identifier.doi10.1002/hep.24709en_US
dc.identifier.pmid21953552-
dc.identifier.scopuseid_2-s2.0-84863011661-
dc.identifier.hkuros203479-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84856407376&selection=ref&src=s&origin=recordpageen_US
dc.identifier.volume55en_US
dc.identifier.issue2en_US
dc.identifier.spage491en_US
dc.identifier.epage505en_US
dc.identifier.eissn1527-3350-
dc.identifier.isiWOS:000299632900018-
dc.publisher.placeUnited Statesen_US
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury-
dc.identifier.scopusauthoridChan, THM=54936485900en_US
dc.identifier.scopusauthoridChen, L=54937809600en_US
dc.identifier.scopusauthoridLiu, M=23489325900en_US
dc.identifier.scopusauthoridHu, L=34770075600en_US
dc.identifier.scopusauthoridZheng, BJ=54935584800en_US
dc.identifier.scopusauthoridPoon, VKM=54934161900en_US
dc.identifier.scopusauthoridHuang, P=54936024100en_US
dc.identifier.scopusauthoridYuan, YF=7402708979en_US
dc.identifier.scopusauthoridHuang, JD=54937814900en_US
dc.identifier.scopusauthoridYang, J=54936874900en_US
dc.identifier.scopusauthoridTsao, GSW=54934305000en_US
dc.identifier.scopusauthoridGuan, XY=7201463221en_US

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