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Article: Granulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance

TitleGranulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistance
Authors
KeywordsMDR1
MRP1
Multiple Drug Resistance
P-glycoprotein
Issue Date2011
PublisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastro
Citation
Gastroenterology, 2011, v. 140 n. 1, p. 344-355 How to Cite?
AbstractBackground & Aims: Chemotherapy is used to treat unresectable liver cancer with marginal efficacy; this might result from hepatic cancer cells with stem cell and chemoresistant features. Gene expression profiling studies have shown that hepatic cancer cells express granulin-epithelin precursor (GEP); we investigated its role in hepatic cancer stem cell functions and chemoresistance. Methods: The effects of GEP and drug transporter signaling on chemoresistance were investigated in hepatic cancer stem cells. We analyzed the expression patterns of 142 clinical samples from liver tumors, adjacent nontumorous liver tissue, and liver tissue from patients who did not have cancer. Results: GEP regulated the expression of the adenosine triphosphatedependent binding cassette (ABC)B5 drug transporter in liver cancer cells. Chemoresistant cells that expressed GEP had increased levels of ABCB5; suppression of ABCB5 sensitized the cells to doxorubicin uptake and apoptosis. Most cells that expressed GEP and ABCB5 also expressed the hepatic cancer stem cell markers CD133 and EpCAM; blocking ABCB5 reduced their expression. Expression levels of GEP and ABCB5 were correlated in human liver tumor samples. ABCB5 levels were increased in liver cancer cells compared with nontumor liver tissue from patients with cirrhosis or hepatitis, or normal liver tissue. ABCB5 expression was associated with the recurrence of hepatocellular carcinoma after partial hepatectomy. Conclusions:: Expression of GEP and ABCB5 in liver cancer stem cells is associated with chemoresistance and reduced survival times of patients with hepatocellular carcinoma. Reagents designed to target these proteins might be developed as therapeutics and given in combination with chemotherapy to patients with liver cancer. © 2011 AGA Institute.
Persistent Identifierhttp://hdl.handle.net/10722/142517
ISSN
2015 Impact Factor: 18.187
2015 SCImago Journal Rankings: 7.170
ISI Accession Number ID
Funding AgencyGrant Number
Pfizer
Sun C. Y. Research Foundation for Hepatobiliary and Pancreatic Surgery
National Natural Science Foundation of China
Hong Kong Research Grants CouncilN_HKU 709/07
HKU 7560/06M
HKU 1/06C
HKU 7/CRG/09
Hong Kong Anti-Cancer Society
University of Hong Kong
Funding Information:

The authors disclose the following: The University of Hong Kong has filed a patent application for the use of the described treatment modality for liver cancer. Dr S. T. Cheung and Dr Fan are inventors of this patent. Dr S. T. Cheung has received Pfizer collaborative research grants. Dr P. F. Y. Cheung, Ms Cheng, and Mr Wong disclose no conflicts. The sponsors had no role in study design as well as in data collection, analysis, and interpretation.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorCheung, STen_HK
dc.contributor.authorCheung, PFYen_HK
dc.contributor.authorCheng, CKCen_HK
dc.contributor.authorWong, NCLen_HK
dc.contributor.authorFan, STen_HK
dc.date.accessioned2011-10-28T02:50:14Z-
dc.date.available2011-10-28T02:50:14Z-
dc.date.issued2011en_HK
dc.identifier.citationGastroenterology, 2011, v. 140 n. 1, p. 344-355en_HK
dc.identifier.issn0016-5085en_HK
dc.identifier.urihttp://hdl.handle.net/10722/142517-
dc.description.abstractBackground & Aims: Chemotherapy is used to treat unresectable liver cancer with marginal efficacy; this might result from hepatic cancer cells with stem cell and chemoresistant features. Gene expression profiling studies have shown that hepatic cancer cells express granulin-epithelin precursor (GEP); we investigated its role in hepatic cancer stem cell functions and chemoresistance. Methods: The effects of GEP and drug transporter signaling on chemoresistance were investigated in hepatic cancer stem cells. We analyzed the expression patterns of 142 clinical samples from liver tumors, adjacent nontumorous liver tissue, and liver tissue from patients who did not have cancer. Results: GEP regulated the expression of the adenosine triphosphatedependent binding cassette (ABC)B5 drug transporter in liver cancer cells. Chemoresistant cells that expressed GEP had increased levels of ABCB5; suppression of ABCB5 sensitized the cells to doxorubicin uptake and apoptosis. Most cells that expressed GEP and ABCB5 also expressed the hepatic cancer stem cell markers CD133 and EpCAM; blocking ABCB5 reduced their expression. Expression levels of GEP and ABCB5 were correlated in human liver tumor samples. ABCB5 levels were increased in liver cancer cells compared with nontumor liver tissue from patients with cirrhosis or hepatitis, or normal liver tissue. ABCB5 expression was associated with the recurrence of hepatocellular carcinoma after partial hepatectomy. Conclusions:: Expression of GEP and ABCB5 in liver cancer stem cells is associated with chemoresistance and reduced survival times of patients with hepatocellular carcinoma. Reagents designed to target these proteins might be developed as therapeutics and given in combination with chemotherapy to patients with liver cancer. © 2011 AGA Institute.en_HK
dc.languageengen_US
dc.publisherWB Saunders Co. The Journal's web site is located at http://www.elsevier.com/locate/gastroen_HK
dc.relation.ispartofGastroenterologyen_HK
dc.subjectMDR1en_HK
dc.subjectMRP1en_HK
dc.subjectMultiple Drug Resistanceen_HK
dc.subjectP-glycoproteinen_HK
dc.subject.meshCarcinoma, Hepatocellular - drug therapy - metabolism - mortality-
dc.subject.meshDrug Resistance, Neoplasm-
dc.subject.meshIntercellular Signaling Peptides and Proteins - genetics - metabolism-
dc.subject.meshLiver Neoplasms - drug therapy - metabolism - mortality-
dc.subject.meshP-Glycoprotein - genetics - metabolism-
dc.titleGranulin-epithelin precursor and ATP-dependent binding cassette (ABC)B5 regulate liver cancer cell chemoresistanceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0016-5085&volume=140&issue=1&spage=344&epage=355&date=2011&atitle=Granulin-epithelin+precursor+and+ATP-dependent+binding+cassette+(ABC)B5+regulate+liver+cancer+cell+chemoresistance-
dc.identifier.emailCheung, ST: stcheung@hkucc.hku.hken_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.authorityCheung, ST=rp00457en_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.description.naturelink_to_subscribed_fulltext-
dc.identifier.doi10.1053/j.gastro.2010.07.049en_HK
dc.identifier.pmid20682318-
dc.identifier.scopuseid_2-s2.0-78650511134en_HK
dc.identifier.hkuros184055en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-78650511134&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume140en_HK
dc.identifier.issue1en_HK
dc.identifier.spage344en_HK
dc.identifier.epage355en_HK
dc.identifier.eissn1528-0012-
dc.identifier.isiWOS:000285503200049-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.relation.projectCirculating cancer biomarkers in liver cancer patients undergoing liver transplantation-
dc.relation.projectGEP as a novel molecular target for liver cancer therapy-
dc.identifier.scopusauthoridCheung, ST=7202473497en_HK
dc.identifier.scopusauthoridCheung, PFY=37030665700en_HK
dc.identifier.scopusauthoridCheng, CKC=37030630100en_HK
dc.identifier.scopusauthoridWong, NCL=37032421100en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK

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