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Article: Overexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis

TitleOverexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasis
Authors
Issue Date2011
PublisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/
Citation
Cancer Research, 2011, v. 71 n. 8, p. 2949-2958 How to Cite?
AbstractThe CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3 or C53/LZAP) regulates apoptosis induced by genotoxic stress. Although CDK5RAP3 has been implicated in cancer progression, its exact role in carcinogenesis is not well established. In this article, we report that CDK5RAP3 has an important prometastatic function in hepatocarcinogenesis. An examination of human hepatocellular carcinoma (HCC) samples revealed at least twofold overexpression of CDK5RAP3 transcripts in 58% (39/67) of HCC specimens when compared with corresponding nontumorous livers. CDK5RAP3 overexpression was associated with more aggressive biological behavior. In HCC cell lines, stable overexpression of CDK5RAP3 promoted, and small interfering RNA-mediated knockdown inhibited, tumorigenic activity and metastatic potential. We found that overexpression of CDK5RAP3 and p21-activated protein kinase 4 (PAK4) correlated in human HCCs, and that CDK5RAP3 was a novel binding partner of PAK4, and this binding enhanced PAK4 activity. siRNA-mediated knockdown of PAK4 in CDK5RAP3-expressing HCC cells reversed the enhanced cell invasiveness mediated by CDK5RAP3 overexpression, implying that PAK4 is essential for CDK5RAP3 function. Taken together, our findings reveal that CDK5RAP3 is widely overexpressed in HCC and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation. © 2011 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/137192
ISSN
2015 Impact Factor: 8.556
2015 SCImago Journal Rankings: 5.372
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grant CouncilN_HKU715/08
HKU 1/06C
7/CRF/09
University of Hong Kong200711159100
Funding Information:

The Hong Kong Research Grant Council (N_HKU715/08, HKU 1/06C and 7/CRF/09) and The University of Hong Kong, Seed Funding Programme (200711159100; to Y. P. Ching), supported this research study.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorMak, GWYen_HK
dc.contributor.authorChan, MMLen_HK
dc.contributor.authorLeong, VYLen_HK
dc.contributor.authorLee, JMFen_HK
dc.contributor.authorYau, TOen_HK
dc.contributor.authorNg, IOLen_HK
dc.contributor.authorChing, YPen_HK
dc.date.accessioned2011-08-26T14:18:32Z-
dc.date.available2011-08-26T14:18:32Z-
dc.date.issued2011en_HK
dc.identifier.citationCancer Research, 2011, v. 71 n. 8, p. 2949-2958en_HK
dc.identifier.issn0008-5472en_HK
dc.identifier.urihttp://hdl.handle.net/10722/137192-
dc.description.abstractThe CDK5 kinase regulatory subunit-associated protein 3 (CDK5RAP3 or C53/LZAP) regulates apoptosis induced by genotoxic stress. Although CDK5RAP3 has been implicated in cancer progression, its exact role in carcinogenesis is not well established. In this article, we report that CDK5RAP3 has an important prometastatic function in hepatocarcinogenesis. An examination of human hepatocellular carcinoma (HCC) samples revealed at least twofold overexpression of CDK5RAP3 transcripts in 58% (39/67) of HCC specimens when compared with corresponding nontumorous livers. CDK5RAP3 overexpression was associated with more aggressive biological behavior. In HCC cell lines, stable overexpression of CDK5RAP3 promoted, and small interfering RNA-mediated knockdown inhibited, tumorigenic activity and metastatic potential. We found that overexpression of CDK5RAP3 and p21-activated protein kinase 4 (PAK4) correlated in human HCCs, and that CDK5RAP3 was a novel binding partner of PAK4, and this binding enhanced PAK4 activity. siRNA-mediated knockdown of PAK4 in CDK5RAP3-expressing HCC cells reversed the enhanced cell invasiveness mediated by CDK5RAP3 overexpression, implying that PAK4 is essential for CDK5RAP3 function. Taken together, our findings reveal that CDK5RAP3 is widely overexpressed in HCC and that overexpression of CDK5RAP3 promotes HCC metastasis through PAK4 activation. © 2011 American Association for Cancer Research.en_HK
dc.languageengen_US
dc.publisherAmerican Association for Cancer Research. The Journal's web site is located at http://cancerres.aacrjournals.org/en_HK
dc.relation.ispartofCancer Researchen_HK
dc.subject.meshCarcinoma, Hepatocellular - enzymology - genetics - metabolism - pathology-
dc.subject.meshCell Growth Processes - physiology-
dc.subject.meshLiver Neoplasms - enzymology - genetics - metabolism - pathology-
dc.subject.meshNerve Tissue Proteins - biosynthesis - genetics-
dc.subject.meshp21-Activated Kinases - metabolism-
dc.titleOverexpression of a novel activator of PAK4, the CDK5 kinase-associated protein CDK5RAP3, promotes hepatocellular carcinoma metastasisen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0008-5472&volume=71&issue=8&spage=2949&epage=2958&date=2011&atitle=Overexpression+of+a+novel+activator+of+PAK4,+the+CDK5+kinase-associated+protein+CDK5RAP3,+promotes+hepatocellular+carcinoma+metastasis-
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_HK
dc.identifier.emailChing, YP:ypching@hku.hken_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/0008-5472.CAN-10-4046en_HK
dc.identifier.pmid21385901-
dc.identifier.scopuseid_2-s2.0-79954581842en_HK
dc.identifier.hkuros189546en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-79954581842&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume71en_HK
dc.identifier.issue8en_HK
dc.identifier.spage2949en_HK
dc.identifier.epage2958en_HK
dc.identifier.eissn1538-7445-
dc.identifier.isiWOS:000289507800015-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.identifier.scopusauthoridMak, GWY=37075049000en_HK
dc.identifier.scopusauthoridChan, MML=35735787800en_HK
dc.identifier.scopusauthoridLeong, VYL=36832636400en_HK
dc.identifier.scopusauthoridLee, JMF=39561284400en_HK
dc.identifier.scopusauthoridYau, TO=7006540669en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK
dc.identifier.scopusauthoridChing, YP=7005431277en_HK

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