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Article: Granulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells

TitleGranulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cells
Authors
KeywordsCancer cell
Immunocompromised patient
Immunohistochemistry
Liver cell carcinoma
Phenotype
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. 12 How to Cite?
AbstractBackground and Aims: Increasing evidence has suggested that hepatocellular carcinoma (HCC) might originate from a distinct subpopulation called cancer stem cells (CSCs), which are responsible for the limited efficacy of conventional therapies. We have previously demonstrated that granulin-epithelin precursor (GEP), a pluripotent growth factor, is upregulated in HCC but not in the adjacent non-tumor, and that GEP is a potential therapeutic target for HCC. Here, we characterized its expression pattern and stem cell properties in fetal and cancerous livers. Methods: Protein expression of GEP in fetal and adult livers was examined in human and mouse models by immunohistochemical staining and flow cytometry. Liver cancer cell lines, isolated based on their GEP and/or ATP-dependent binding cassette (ABC) drug transporter ABCB5 expression, were evaluated for hepatic CSC properties in terms of colony formation, chemoresistance and tumorigenicity. Results: We demonstrated that GEP was a hepatic oncofetal protein that expressed in the fetal livers, but not in the normal adult livers. Importantly, GEP+ fetal liver cells co-expressed the embryonic stem (ES) cell-related signaling molecules including β-catenin, Oct4, Nanog, Sox2 and DLK1, and also hepatic CSC-markers CD133, EpCAM and ABCB5. Phenotypic characterization in HCC clinical specimens and cell lines revealed that GEP+ cancer cells co-expressed these stem cell markers similarly as the GEP+ fetal liver cells. Furthermore, GEP was shown to regulate the expression of ES cell-related signaling molecules β-catenin, Oct4, Nanog, and Sox2. Isolated GEP high cancer cells showed enhanced colony formation ability and chemoresistance when compared with the GEP low counterparts. Co-expression of GEP and ABCB5 better defined the CSC populations with enhanced tumorigenic ability in immunocompromised mice. Conclusions: Our findings demonstrate that GEP is a hepatic oncofetal protein regulating ES cell-related signaling molecules. Co-expression of GEP and ABCB5 further enriches a subpopulation with enhanced CSC properties. The current data provide new insight into the therapeutic strategy. © 2011 Cheung et al.
Persistent Identifierhttp://hdl.handle.net/10722/144591
ISSN
2015 Impact Factor: 3.057
2015 SCImago Journal Rankings: 1.395
PubMed Central ID
ISI Accession Number ID
Funding AgencyGrant Number
Sun C.Y. Research Foundation for Hepatobiliary and Pancreatic Surgery
National Natural Science Foundation of China
Hong Kong Research Grants CouncilN_HKU 709/07
HKU7/CRG/09
University of Hong Kong
Funding Information:

This study was supported in part by Sun C.Y. Research Foundation for Hepatobiliary and Pancreatic Surgery, National Natural Science Foundation of China and the Hong Kong Research Grants Council (N_HKU 709/07, HKU7/CRG/09), the Seed Funding Program and Small Project Funding Program of the University of Hong Kong. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References
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DC FieldValueLanguage
dc.contributor.authorCheung, PFYen_HK
dc.contributor.authorCheng, CKCen_HK
dc.contributor.authorWong, NCLen_HK
dc.contributor.authorHo, JCYen_HK
dc.contributor.authorYip, CWen_HK
dc.contributor.authorLui, VCHen_HK
dc.contributor.authorCheung, ANYen_HK
dc.contributor.authorFan, STen_HK
dc.contributor.authorCheung, STen_HK
dc.date.accessioned2012-02-03T06:15:05Z-
dc.date.available2012-02-03T06:15:05Z-
dc.date.issued2011en_HK
dc.identifier.citationPlos One, 2011, v. 6 n. 12en_HK
dc.identifier.issn1932-6203en_HK
dc.identifier.urihttp://hdl.handle.net/10722/144591-
dc.description.abstractBackground and Aims: Increasing evidence has suggested that hepatocellular carcinoma (HCC) might originate from a distinct subpopulation called cancer stem cells (CSCs), which are responsible for the limited efficacy of conventional therapies. We have previously demonstrated that granulin-epithelin precursor (GEP), a pluripotent growth factor, is upregulated in HCC but not in the adjacent non-tumor, and that GEP is a potential therapeutic target for HCC. Here, we characterized its expression pattern and stem cell properties in fetal and cancerous livers. Methods: Protein expression of GEP in fetal and adult livers was examined in human and mouse models by immunohistochemical staining and flow cytometry. Liver cancer cell lines, isolated based on their GEP and/or ATP-dependent binding cassette (ABC) drug transporter ABCB5 expression, were evaluated for hepatic CSC properties in terms of colony formation, chemoresistance and tumorigenicity. Results: We demonstrated that GEP was a hepatic oncofetal protein that expressed in the fetal livers, but not in the normal adult livers. Importantly, GEP+ fetal liver cells co-expressed the embryonic stem (ES) cell-related signaling molecules including β-catenin, Oct4, Nanog, Sox2 and DLK1, and also hepatic CSC-markers CD133, EpCAM and ABCB5. Phenotypic characterization in HCC clinical specimens and cell lines revealed that GEP+ cancer cells co-expressed these stem cell markers similarly as the GEP+ fetal liver cells. Furthermore, GEP was shown to regulate the expression of ES cell-related signaling molecules β-catenin, Oct4, Nanog, and Sox2. Isolated GEP high cancer cells showed enhanced colony formation ability and chemoresistance when compared with the GEP low counterparts. Co-expression of GEP and ABCB5 better defined the CSC populations with enhanced tumorigenic ability in immunocompromised mice. Conclusions: Our findings demonstrate that GEP is a hepatic oncofetal protein regulating ES cell-related signaling molecules. Co-expression of GEP and ABCB5 further enriches a subpopulation with enhanced CSC properties. The current data provide new insight into the therapeutic strategy. © 2011 Cheung 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.subjectCancer cell-
dc.subjectImmunocompromised patient-
dc.subjectImmunohistochemistry-
dc.subjectLiver cell carcinoma-
dc.subjectPhenotype-
dc.titleGranulin-epithelin precursor is an oncofetal protein defining hepatic cancer stem cellsen_HK
dc.typeArticleen_HK
dc.identifier.emailLui, VCH: vchlui@hkucc.hku.hken_HK
dc.identifier.emailCheung, ANY: anycheun@hkucc.hku.hken_HK
dc.identifier.emailFan, ST: stfan@hku.hken_HK
dc.identifier.emailCheung, ST: stcheung@hkucc.hku.hken_HK
dc.identifier.authorityLui, VCH=rp00363en_HK
dc.identifier.authorityCheung, ANY=rp00542en_HK
dc.identifier.authorityFan, ST=rp00355en_HK
dc.identifier.authorityCheung, ST=rp00457en_HK
dc.description.naturepublished_or_final_version-
dc.identifier.doi10.1371/journal.pone.0028246en_HK
dc.identifier.pmid22194816-
dc.identifier.pmcidPMC3241621-
dc.identifier.scopuseid_2-s2.0-83455186991en_HK
dc.identifier.hkuros198343en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-83455186991&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume6en_HK
dc.identifier.issue12en_HK
dc.identifier.eissn1932-6203-
dc.identifier.isiWOS:000298664400005-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectCirculating cancer biomarkers in liver cancer patients undergoing liver transplantation-
dc.identifier.scopusauthoridCheung, PFY=37030665700en_HK
dc.identifier.scopusauthoridCheng, CKC=37030630100en_HK
dc.identifier.scopusauthoridWong, NCL=37032421100en_HK
dc.identifier.scopusauthoridHo, JCY=7402650173en_HK
dc.identifier.scopusauthoridYip, CW=54685625700en_HK
dc.identifier.scopusauthoridLui, VCH=7004231344en_HK
dc.identifier.scopusauthoridCheung, ANY=54927484100en_HK
dc.identifier.scopusauthoridFan, ST=7402678224en_HK
dc.identifier.scopusauthoridCheung, ST=7202473497en_HK
dc.identifier.citeulike10163549-

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