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Article: Aberrant Polo-like kinase 1-Cdc25A pathway in metastatic hepatocellular carcinoma

TitleAberrant Polo-like kinase 1-Cdc25A pathway in metastatic hepatocellular carcinoma
Authors
Issue Date2008
PublisherAmerican Association for Cancer Research
Citation
Clinical Cancer Research, 2008, v. 14 n. 21, p. 6813-6820 How to Cite?
AbstractPurpose: Most studies on pathogenesis of tumor metastasis focus on cell adhesion and migration. Little is understood of how cell cycle pathways critically affect cell fate of metastatic cells and their sensitivity to anticancer drugs. In this study, we investigated cell cycle checkpoint progression and regulation in the presence of cisplatin in metastatic hepatocellular carcinoma (HCC) cells. Experimental Design: Cisplatin-mediated cell cycle progression and Polo-like kinase 1 (Plk1)-Cdc25A pathway were compared between metastatic and nonmetastatic HCC cells by flow cytometry,Western blots, and reverse transcription-PCR. Cdc25A expression in clinical HCC samples was detected using immunohistochemistry and its association with clinical HCC metastasis was analyzed. Results: Cisplatin induced degradation of Cdc25A in nonmetastatic HCC cells but not in metastatic HCC cells. Hence, metastatic HCC cells showed defective S-M cell cycle phase arrest and continued to enter mitosis. Tumor expression of Cdc25A was strongly associated with metastatic diseases in HCC patients, and elevated Cdc25A expression significantly correlated with HCC tumor-node-metastasis staging and venous invasion. Metastatic HCC cells did not show down-regulation of Plk1 that was normally induced by DNA damage. Blockage of Plk1 expression in metastatic HCC cells initiated Cdc25A degradation in response to DNA damage, suggesting that Plk1 could be an upstream regulator of Cdc25A. Deregulated Plk1-Cdc25A pathway in metastatic HCC cells and primary tumors did not result in drug-induced mitotic catastrophe but rather in accumulation of damaged DNA due to checkpoint adaptation. Conclusions: Metastatic HCC cells showed a defective S-M checkpoint following cisplatin treatment and potential aberrant checkpoint adaptation, which might result from deregulation of Plk1-Cdc25A pathway. ©2008 American Association for Cancer Research.
Persistent Identifierhttp://hdl.handle.net/10722/59942
ISSN
2015 Impact Factor: 8.738
2015 SCImago Journal Rankings: 5.314
ISI Accession Number ID
Funding AgencyGrant Number
Research Grants Council of Hong KongHKU777907M
59002
SCY Research Foundation
Funding Information:

Research Grants Council of Hong Kong grant HKU777907M, HKU grant 59002, and SCY Research Foundation.

References

 

DC FieldValueLanguage
dc.contributor.authorXiao, QWen_HK
dc.contributor.authorYong, QZen_HK
dc.contributor.authorLui, KSen_HK
dc.contributor.authorCai, Qen_HK
dc.contributor.authorLu, Pen_HK
dc.contributor.authorPoon, RTen_HK
dc.date.accessioned2010-05-31T04:00:36Z-
dc.date.available2010-05-31T04:00:36Z-
dc.date.issued2008en_HK
dc.identifier.citationClinical Cancer Research, 2008, v. 14 n. 21, p. 6813-6820en_HK
dc.identifier.issn1078-0432en_HK
dc.identifier.urihttp://hdl.handle.net/10722/59942-
dc.description.abstractPurpose: Most studies on pathogenesis of tumor metastasis focus on cell adhesion and migration. Little is understood of how cell cycle pathways critically affect cell fate of metastatic cells and their sensitivity to anticancer drugs. In this study, we investigated cell cycle checkpoint progression and regulation in the presence of cisplatin in metastatic hepatocellular carcinoma (HCC) cells. Experimental Design: Cisplatin-mediated cell cycle progression and Polo-like kinase 1 (Plk1)-Cdc25A pathway were compared between metastatic and nonmetastatic HCC cells by flow cytometry,Western blots, and reverse transcription-PCR. Cdc25A expression in clinical HCC samples was detected using immunohistochemistry and its association with clinical HCC metastasis was analyzed. Results: Cisplatin induced degradation of Cdc25A in nonmetastatic HCC cells but not in metastatic HCC cells. Hence, metastatic HCC cells showed defective S-M cell cycle phase arrest and continued to enter mitosis. Tumor expression of Cdc25A was strongly associated with metastatic diseases in HCC patients, and elevated Cdc25A expression significantly correlated with HCC tumor-node-metastasis staging and venous invasion. Metastatic HCC cells did not show down-regulation of Plk1 that was normally induced by DNA damage. Blockage of Plk1 expression in metastatic HCC cells initiated Cdc25A degradation in response to DNA damage, suggesting that Plk1 could be an upstream regulator of Cdc25A. Deregulated Plk1-Cdc25A pathway in metastatic HCC cells and primary tumors did not result in drug-induced mitotic catastrophe but rather in accumulation of damaged DNA due to checkpoint adaptation. Conclusions: Metastatic HCC cells showed a defective S-M checkpoint following cisplatin treatment and potential aberrant checkpoint adaptation, which might result from deregulation of Plk1-Cdc25A pathway. ©2008 American Association for Cancer Research.en_HK
dc.languageengen_HK
dc.publisherAmerican Association for Cancer Researchen_HK
dc.relation.ispartofClinical Cancer Researchen_HK
dc.titleAberrant Polo-like kinase 1-Cdc25A pathway in metastatic hepatocellular carcinomaen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=1078-0432&volume=14&issue=21&spage=6813&epage=6820&date=2008&atitle=Aberrant+Polo-like+kinase+1-Cdc25A+pathway+in+metastatic+hepatocellular+carcinomaen_HK
dc.identifier.emailXiao, QW: xqwang@hkucc.hku.hken_HK
dc.identifier.emailPoon, RT: poontp@hkucc.hku.hken_HK
dc.identifier.authorityXiao, QW=rp00507en_HK
dc.identifier.authorityPoon, RT=rp00446en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1158/1078-0432.CCR-08-0626en_HK
dc.identifier.scopuseid_2-s2.0-58149214374en_HK
dc.identifier.hkuros146277en_HK
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-58149214374&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume14en_HK
dc.identifier.issue21en_HK
dc.identifier.spage6813en_HK
dc.identifier.epage6820en_HK
dc.identifier.eissn1557-3265-
dc.identifier.isiWOS:000260732200014-
dc.publisher.placeUnited Statesen_HK
dc.identifier.scopusauthoridXiao, QW=17343159900en_HK
dc.identifier.scopusauthoridYong, QZ=24768082800en_HK
dc.identifier.scopusauthoridLui, KS=25936451500en_HK
dc.identifier.scopusauthoridCai, Q=25935876300en_HK
dc.identifier.scopusauthoridLu, P=55041426400en_HK
dc.identifier.scopusauthoridPoon, RT=7103097223en_HK

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