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Article: Hepatocyte-specific activation of NF-κB does not aggravate chemical hepatocarcinogenesis in transgenic mice

TitleHepatocyte-specific activation of NF-κB does not aggravate chemical hepatocarcinogenesis in transgenic mice
Authors
KeywordsChemical carcinogenesis
Diethylnitrosamine
IκB
IKK
Liver
NF-κB
Signal transduction
Issue Date2009
PublisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130
Citation
Journal Of Pathology, 2009, v. 217 n. 3, p. 353-361 How to Cite?
AbstractThe NF-κB signalling pathway plays important roles in liver organogenesis and cardnogenesis. Mouse embryos deficient in IKKβ die in mid-gestation, due to excessive apoptosis of hepatoblasts. Although activation of the NF-κB signalling pathway has been demonstrated in human hepatocellular carcinoma, the role of NF-κB is controversial. Here, we have generated transgenic mice in which a constitutively active form of IKKβ was expressed in a hepatocyte-specific manner. Using electrophoretic mobility shift assay, we documented increased NF-κB activities and up-regulated levels of NF-κB downstream target genes, Bcl-xL and STAT5, in the transgenic mouse livers. These results confirmed that the NF-κB pathway was activated in the livers of the transgenic mice. However, there was no significant difference in tumour formation between transgenic and wild-type mice up to an age of 50 weeks. When we treated the transgenic mice with the chemical carcinogen diethylnitrosamine (DEN), we observed no significant differences in the incidence and size of liver tumours formed in these mice with and without DEN treatment at 35 weeks of age, suggesting that the activated NF-κB pathway in the livers of the transgenic mice did not enhance hepatocarcinogenesis. Interestingly, some of the transient transgenic embryos (E12.5) had abnormal excessive accumulation of nucleated red blood cells in their developing livers. In summary, NF-κB activation in hepatocytes did not significantly affect chemical hepatocarcinogenesis. In addition, the TTR/IKKCA transgenic mice may serve as a useful model for studying the role of NF-κB activation in hepatocarcinogenesis as well as inflammatory and metabolic diseases. Copyright © 2008 Pathological Society of Great Britain and Ireland.
Persistent Identifierhttp://hdl.handle.net/10722/129101
ISSN
2015 Impact Factor: 7.381
2015 SCImago Journal Rankings: 4.176
ISI Accession Number ID
Funding AgencyGrant Number
Hong Kong Research Grants Council General Research FundHKU 7329/02M
RGC Collaborative Research FundHKU 1/06C
Funding Information:

This study was supported by a Hong Kong Research Grants Council General Research Fund (HKU 7329/02M) and RGC Collaborative Research Fund (HKU 1/06C). IOL Ng is Loke Yew Professor in Pathology.

References
Grants

 

DC FieldValueLanguage
dc.contributor.authorYau, TOen_HK
dc.contributor.authorChan, CFen_HK
dc.contributor.authorLam, SGSen_HK
dc.contributor.authorCheung, OFen_HK
dc.contributor.authorChing, YPen_HK
dc.contributor.authorJin, DYen_HK
dc.contributor.authorSham, MHen_HK
dc.contributor.authorNg, IOLen_HK
dc.date.accessioned2010-12-23T08:32:31Z-
dc.date.available2010-12-23T08:32:31Z-
dc.date.issued2009en_HK
dc.identifier.citationJournal Of Pathology, 2009, v. 217 n. 3, p. 353-361en_HK
dc.identifier.issn0022-3417en_HK
dc.identifier.urihttp://hdl.handle.net/10722/129101-
dc.description.abstractThe NF-κB signalling pathway plays important roles in liver organogenesis and cardnogenesis. Mouse embryos deficient in IKKβ die in mid-gestation, due to excessive apoptosis of hepatoblasts. Although activation of the NF-κB signalling pathway has been demonstrated in human hepatocellular carcinoma, the role of NF-κB is controversial. Here, we have generated transgenic mice in which a constitutively active form of IKKβ was expressed in a hepatocyte-specific manner. Using electrophoretic mobility shift assay, we documented increased NF-κB activities and up-regulated levels of NF-κB downstream target genes, Bcl-xL and STAT5, in the transgenic mouse livers. These results confirmed that the NF-κB pathway was activated in the livers of the transgenic mice. However, there was no significant difference in tumour formation between transgenic and wild-type mice up to an age of 50 weeks. When we treated the transgenic mice with the chemical carcinogen diethylnitrosamine (DEN), we observed no significant differences in the incidence and size of liver tumours formed in these mice with and without DEN treatment at 35 weeks of age, suggesting that the activated NF-κB pathway in the livers of the transgenic mice did not enhance hepatocarcinogenesis. Interestingly, some of the transient transgenic embryos (E12.5) had abnormal excessive accumulation of nucleated red blood cells in their developing livers. In summary, NF-κB activation in hepatocytes did not significantly affect chemical hepatocarcinogenesis. In addition, the TTR/IKKCA transgenic mice may serve as a useful model for studying the role of NF-κB activation in hepatocarcinogenesis as well as inflammatory and metabolic diseases. Copyright © 2008 Pathological Society of Great Britain and Ireland.en_HK
dc.languageengen_US
dc.publisherJohn Wiley & Sons. The Journal's web site is located at http://www3.interscience.wiley.com/cgi-bin/jhome/1130en_HK
dc.relation.ispartofJournal of Pathologyen_HK
dc.rightsCreative Commons: Attribution 3.0 Hong Kong License-
dc.rightsJournal of Pathology. Copyright © John Wiley & Sons.-
dc.rightsThis is a preprint of an article published in Journal of Pathology, 2009, v. 217 n. 3, p. 353-361-
dc.subjectChemical carcinogenesisen_HK
dc.subjectDiethylnitrosamineen_HK
dc.subjectIκBen_HK
dc.subjectIKKen_HK
dc.subjectLiveren_HK
dc.subjectNF-κBen_HK
dc.subjectSignal transductionen_HK
dc.subject.meshCarcinoma, Hepatocellular - chemically induced - metabolism-
dc.subject.meshHepatocytes - metabolism-
dc.subject.meshI-kappa B Kinase - genetics - metabolism-
dc.subject.meshLiver Neoplasms, Experimental - chemically induced - metabolism-
dc.subject.meshNF-kappa B - analysis - metabolism-
dc.titleHepatocyte-specific activation of NF-κB does not aggravate chemical hepatocarcinogenesis in transgenic miceen_HK
dc.typeArticleen_HK
dc.identifier.openurlhttp://library.hku.hk:4550/resserv?sid=HKU:IR&issn=0022-3417&volume=217&issue=3&spage=353&epage=361&date=2009&atitle=Hepatocyte-specific+activation+of+NF-kB+does+not+aggravate+chemical+hepatocarcinogenesis+in+transgenic+mice-
dc.identifier.emailChing, YP:ypching@hku.hken_HK
dc.identifier.emailJin, DY:dyjin@hkucc.hku.hken_HK
dc.identifier.emailSham, MH:mhsham@hkucc.hku.hken_HK
dc.identifier.emailNg, IOL:iolng@hkucc.hku.hken_HK
dc.identifier.authorityChing, YP=rp00469en_HK
dc.identifier.authorityJin, DY=rp00452en_HK
dc.identifier.authoritySham, MH=rp00380en_HK
dc.identifier.authorityNg, IOL=rp00335en_HK
dc.description.naturepostprint-
dc.identifier.doi10.1002/path.2451en_HK
dc.identifier.pmid19090486-
dc.identifier.scopuseid_2-s2.0-60549116315en_HK
dc.identifier.hkuros176661en_US
dc.relation.referenceshttp://www.scopus.com/mlt/select.url?eid=2-s2.0-60549116315&selection=ref&src=s&origin=recordpageen_HK
dc.identifier.volume217en_HK
dc.identifier.issue3en_HK
dc.identifier.spage353en_HK
dc.identifier.epage361en_HK
dc.identifier.isiWOS:000263076900003-
dc.publisher.placeUnited Kingdomen_HK
dc.relation.projectMolecular pathology of liver cancer - a multidisciplinary study-
dc.relation.projectDysregulation of NF-[kappa]B signaling in liver cancer-
dc.identifier.scopusauthoridYau, TO=7006540669en_HK
dc.identifier.scopusauthoridChan, CF=8277448300en_HK
dc.identifier.scopusauthoridLam, SGS=35077630000en_HK
dc.identifier.scopusauthoridCheung, OF=16311432900en_HK
dc.identifier.scopusauthoridChing, YP=7005431277en_HK
dc.identifier.scopusauthoridJin, DY=7201973614en_HK
dc.identifier.scopusauthoridSham, MH=7003729109en_HK
dc.identifier.scopusauthoridNg, IOL=7102753722en_HK

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