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Article: The role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in hepatocellular carcinoma

TitleThe role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in hepatocellular carcinoma
Authors
KeywordsCisplatin
Cancer cell culture
Enzyme activity
Multidrug resistance protein 1
Liver cell carcinoma
Issue Date2011
PublisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.action
Citation
Plos One, 2011, v. 6 n. 11 How to Cite?
AbstractAims: We previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism. Methodology/Principal Findings: Stable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples. Conclusions: Our results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes. © 2011 Geng et al.
Persistent Identifierhttp://hdl.handle.net/10722/144594
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant Council Hong Kong7574/06M
HKU5/CRF/08
Funding Information:

This study was supported by the General Research Fund (7574/06M) and Collaborative Research Fund (HKU5/CRF/08) of the Research Grant Council Hong Kong. http://www.ugc.edu.hk/eng/ugc/index.htm. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorGeng, Wen_HK
dc.contributor.authorNg, KTPen_HK
dc.contributor.authorSun, CKWen_HK
dc.contributor.authorYau, WLen_HK
dc.contributor.authorLiu, XBen_HK
dc.contributor.authorCheng, Qen_HK
dc.contributor.authorPoon, RTPen_HK
dc.contributor.authorLo, CMen_HK
dc.contributor.authorMan, Ken_HK
dc.contributor.authorFan, STen_HK
dc.date.accessioned2012-02-03T06:15:07Z-
dc.date.available2012-02-03T06:15:07Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos One, 2011, v. 6 n. 11en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/144594-
dc.description.abstractAims: We previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism. Methodology/Principal Findings: Stable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples. Conclusions: Our results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes. © 2011 Geng et al.en_HK
dc.languageengen_US
dc.publisherPublic Library of Science. The Journal's web site is located at http://www.plosone.org/home.actionen_HK
dc.relation.ispartofPLoS ONEen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.subjectCisplatin-
dc.subjectCancer cell culture-
dc.subjectEnzyme activity-
dc.subjectMultidrug resistance protein 1-
dc.subjectLiver cell carcinoma-
dc.titleThe role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in hepatocellular carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.emailNg, KTP: ledodes@hku.hken_HK
dc.identifier.emailPoon, RTP: poontp@hku.hken_HK
dc.identifier.emailLo, CM: chungmlo@hkucc.hku.hken_HK
dc.identifier.emailMan, K: kwanman@hku.hken_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.authorityNg, KTP=rp01720en_HK
dc.identifier.authorityPoon, RTP=rp00446en_HK
dc.identifier.authorityLo, CM=rp00412en_HK
dc.identifier.authorityMan, K=rp00417en_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0027362en_HK
dc.identifier.pmid22096562-
dc.identifier.pmcidPMC3212555-
dc.identifier.scopuseid_2-s2.0-80655141609en_HK
dc.identifier.hkuros198347en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-80655141609&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue11en_HK
dc.identifier.spagee27362en_US
dc.identifier.epagee27362en_US
dc.identifier.isiWOS:000297350800049-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectLiver Transplantation Research Centre: A Multidisciplinary Study for Liver Graft Injury-
dc.identifier.scopusauthoridGeng, W=54412151800en_HK
dc.identifier.scopusauthoridNg, KTP=7403178513en_HK
dc.identifier.scopusauthoridSun, CKW=7404248685en_HK
dc.identifier.scopusauthoridYau, WL=55177535200en_HK
dc.identifier.scopusauthoridLiu, XB=17435186900en_HK
dc.identifier.scopusauthoridCheng, Q=16024087700en_HK
dc.identifier.scopusauthoridPoon, RTP=7103097223en_HK
dc.identifier.scopusauthoridLo, CM=7401771672en_HK
dc.identifier.scopusauthoridMan, K=7101754072en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK

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