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Article: CD133 + liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling

TitleCD133 + liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signaling
Authors
Issue Date2012
PublisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/
Citation
Hepatology, 2012, v. 55 n. 3, p. 807-820 How to Cite?
AbstractA novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133 + liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133 + cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133 + liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133 + liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133 + liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133 + liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling. Conclusion: CD133 + liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade. (Hepatology 2012) © 2011 American Association for the Study of Liver Diseases.
Persistent Identifierhttp://hdl.handle.net/10722/148686
ISSN
2015 Impact Factor: 11.711
2015 SCImago Journal Rankings: 4.752
ISI Accession Number ID
Funding AgencyGrant Number
Research Grant CouncilHKU 1/06C
HKU 5/CRF/08
HKU 7/CRG/09
University of Hong Kong Strategic Research Theme in Cancer
Funding Information:

Funded by: Sir Michael and Lady Kadoorie Funded Research into Cancer Genetics, Research Grant Council General Research Fund, Research Grant Council Collaborative Research Fund (HKU 1/06C, HKU 5/CRF/08 and HKU 7/CRG/09) and the University of Hong Kong Strategic Research Theme in Cancer.

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DC FieldValueLanguage
dc.contributor.authorTang, KHen_HK
dc.contributor.authorMa, Sen_HK
dc.contributor.authorLee, TKen_HK
dc.contributor.authorChan, YPen_HK
dc.contributor.authorKwan, PSen_HK
dc.contributor.authorTong, CMen_HK
dc.contributor.authorNg, IOen_HK
dc.contributor.authorMan, Ken_HK
dc.contributor.authorTo, KFen_HK
dc.contributor.authorLai, PBen_HK
dc.contributor.authorLo, CMen_HK
dc.contributor.authorGuan, XYen_HK
dc.contributor.authorChan, KWen_HK
dc.date.accessioned2012-05-29T06:14:40Z-
dc.date.available2012-05-29T06:14:40Z-
dc.date.issued2012en_HK
dc.identifier.citationHepatology, 2012, v. 55 n. 3, p. 807-820en_HK
dc.identifier.issn0270-9139en_HK
dc.identifier.urihttp://hdl.handle.net/10722/148686-
dc.description.abstractA novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). We previously identified a TIC population derived from hepatocellular carcinoma (HCC) that is characterized by membrane expression of CD133. Here, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133 + liver TICs obtained from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133 + cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133 + liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis, and initiate tumors. In further support of these observations, IL-8 repression in CD133 + liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be preferentially expressed in CD133 + liver TICs. Addition of exogenous NTS resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, both key components of the mitogen-activated protein kinase (MAPK) pathway. Enhanced IL-8 secretion by CD133 + liver TICs can in turn activate an IL-8-dependent feedback loop that signals through the MAPK pathway. Further, in its role as a liver TIC marker CD133 also plays a functional part in regulating tumorigenesis of liver TICs by way of regulating NTS, IL-8, CXCL1, and MAPK signaling. Conclusion: CD133 + liver TICs promote angiogenesis, tumorigenesis, and self-renewal through NTS-induced activation of the IL-8 signaling cascade. (Hepatology 2012) © 2011 American Association for the Study of Liver Diseases.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons, Inc. The Journal's web site is located at http://www.hepatology.org/en_HK
dc.relation.ispartofHepatologyen_HK
dc.rightsHepatology. Copyright © John Wiley & Sons, Inc.-
dc.subject.meshAntigens, CD - genetics - metabolism-
dc.subject.meshCell Proliferation-
dc.subject.meshChemokine CXCL1 - physiology-
dc.subject.meshGlycoproteins - deficiency - genetics - metabolism-
dc.subject.meshInterleukin-8 - deficiency - genetics - physiology-
dc.titleCD133 + liver tumor-initiating cells promote tumor angiogenesis, growth, and self-renewal through neurotensin/interleukin-8/CXCL1 signalingen_HK
dc.typeArticleen_HK
dc.identifier.emailMa, S: sma@pathology.hku.hken_HK
dc.identifier.emailLee, TK: tkwlee@hkucc.hku.hken_HK
dc.identifier.emailMan, K: kwanman@hkucc.hku.hken_HK
dc.identifier.emailGuan, XY: xyguan@hkucc.hku.hken_HK
dc.identifier.emailChan, KW: hrmtckw@hku.hken_HK
dc.identifier.authorityMa, S=rp00506en_HK
dc.identifier.authorityLee, TK=rp00447en_HK
dc.identifier.authorityMan, K=rp00417en_HK
dc.identifier.authorityGuan, XY=rp00454en_HK
dc.identifier.authorityChan, KW=rp00330en_HK
dc.description.naturelink_to_subscribed_fulltexten_US
dc.identifier.doi10.1002/hep.24739en_HK
dc.identifier.pmid21994122-
dc.identifier.scopuseid_2-s2.0-84862777489en_HK
dc.identifier.hkuros197820-
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-84862777489&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume55en_HK
dc.identifier.issue3en_HK
dc.identifier.spage807en_HK
dc.identifier.epage820en_HK
dc.identifier.eissn1527-3350-
dc.identifier.isiWOS:000300699900018-
dc.publisher.placeUnited Statesen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.identifier.scopusauthoridTang, KH=55261608900en_HK
dc.identifier.scopusauthoridMa, S=16444895800en_HK
dc.identifier.scopusauthoridLee, TK=7501439435en_HK
dc.identifier.scopusauthoridChan, YP=14009821700en_HK
dc.identifier.scopusauthoridKwan, PS=36698058700en_HK
dc.identifier.scopusauthoridTong, CM=46062579200en_HK
dc.identifier.scopusauthoridNg, IO=55261303200en_HK
dc.identifier.scopusauthoridMan, K=7101754072en_HK
dc.identifier.scopusauthoridTo, KF=7101911940en_HK
dc.identifier.scopusauthoridLai, PB=35311166300en_HK
dc.identifier.scopusauthoridLo, CM=55261732500en_HK
dc.identifier.scopusauthoridGuan, XY=7201463221en_HK
dc.identifier.scopusauthoridChan, KW=16444133100en_HK
dc.identifier.citeulike9913596-

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