Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma

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dc.contributor.authorMelis, Marta
dc.contributor.authorDiaz, Giacomo
dc.contributor.authorKleiner, David E
dc.contributor.authorZamboni, Fausto
dc.contributor.authorKabat, Juraj
dc.contributor.authorLai, Jinping
dc.contributor.authorMogavero, Giulia
dc.contributor.authorTice, Ashley
dc.contributor.authorEngle, Ronald E
dc.contributor.authorBecker, Steven
dc.contributor.authorBrown, Charles R
dc.contributor.authorHanson, Jeffrey C
dc.contributor.authorRodriguez-Canales, Jaime
dc.contributor.authorEmmert-Buck, Michael
dc.contributor.authorGovindarajan, Sugantha
dc.contributor.authorKew, Michael
dc.contributor.authorFarci, Patrizia
dc.date.accessioned2015-07-30T04:10:40Z
dc.date.available2015-07-30T04:10:40Z
dc.date.issued2014-08-21
dc.date.updated2015-01-15T17:58:45Z
dc.description.abstractAbstract Background The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by studying multiple areas of the same liver from patients with HCC. Methods We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes along with the intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center from individual livers of 11 patients with HCC and on selected LCM samples. HBV markers in liver and serum were determined by real-time polymerase chain reaction (PCR) and confocal immunofluorescence. Results Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HB surface antigen (HBsAg). The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipids and fatty acids, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARα/RXRα nuclear receptors, comprising PGC-1α and FOXO1, two key regulators critically involved not only in the metabolic functions of the liver but also in the life cycle of HBV, acting as essential transcription factors for viral gene expression. These findings were confirmed by gene expression of microdissected hepatocytes. Moreover, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen genes, NUF2 and TTK. Conclusions Integrated gene expression profiling of whole liver tissue with that of microdissected hepatocytes demonstrated that HBV-associated HCC is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis, opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets.
dc.identifier.apacitationMelis, M., Diaz, G., Kleiner, D. E., Zamboni, F., Kabat, J., Lai, J., ... Farci, P. (2014). Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma. <i>Journal of Translational Medicine</i>, http://hdl.handle.net/11427/13626en_ZA
dc.identifier.chicagocitationMelis, Marta, Giacomo Diaz, David E Kleiner, Fausto Zamboni, Juraj Kabat, Jinping Lai, Giulia Mogavero, et al "Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma." <i>Journal of Translational Medicine</i> (2014) http://hdl.handle.net/11427/13626en_ZA
dc.identifier.citationMelis, M., Diaz, G., Kleiner, D. E., Zamboni, F., Kabat, J., Lai, J., ... & Farci, P. (2014). Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus-associated hepatocellular carcinoma. Journal of translational medicine, 12(1), 1-15.
dc.identifier.ris TY - Journal Article AU - Melis, Marta AU - Diaz, Giacomo AU - Kleiner, David E AU - Zamboni, Fausto AU - Kabat, Juraj AU - Lai, Jinping AU - Mogavero, Giulia AU - Tice, Ashley AU - Engle, Ronald E AU - Becker, Steven AU - Brown, Charles R AU - Hanson, Jeffrey C AU - Rodriguez-Canales, Jaime AU - Emmert-Buck, Michael AU - Govindarajan, Sugantha AU - Kew, Michael AU - Farci, Patrizia AB - Abstract Background The molecular mechanisms whereby hepatitis B virus (HBV) induces hepatocellular carcinoma (HCC) remain elusive. We used genomic and molecular techniques to investigate host-virus interactions by studying multiple areas of the same liver from patients with HCC. Methods We compared the gene signature of whole liver tissue (WLT) versus laser capture-microdissected (LCM) hepatocytes along with the intrahepatic expression of HBV. Gene expression profiling was performed on up to 17 WLT specimens obtained at various distances from the tumor center from individual livers of 11 patients with HCC and on selected LCM samples. HBV markers in liver and serum were determined by real-time polymerase chain reaction (PCR) and confocal immunofluorescence. Results Analysis of 5 areas of the liver showed a sharp change in gene expression between the immediate perilesional area and tumor periphery that correlated with a significant decrease in the intrahepatic expression of HB surface antigen (HBsAg). The tumor was characterized by a large preponderance of down-regulated genes, mostly involved in the metabolism of lipids and fatty acids, glucose, amino acids and drugs, with down-regulation of pathways involved in the activation of PXR/RXR and PPARα/RXRα nuclear receptors, comprising PGC-1α and FOXO1, two key regulators critically involved not only in the metabolic functions of the liver but also in the life cycle of HBV, acting as essential transcription factors for viral gene expression. These findings were confirmed by gene expression of microdissected hepatocytes. Moreover, LCM of malignant hepatocytes also revealed up-regulation of unique genes associated with cancer and signaling pathways, including two novel HCC-associated cancer testis antigen genes, NUF2 and TTK. Conclusions Integrated gene expression profiling of whole liver tissue with that of microdissected hepatocytes demonstrated that HBV-associated HCC is characterized by a metabolism switch-off and by a significant reduction in HBsAg. LCM proved to be a critical tool to validate gene signatures associated with HCC and to identify genes that may play a role in hepatocarcinogenesis, opening new perspectives for the discovery of novel diagnostic markers and therapeutic targets. DA - 2014-08-21 DB - OpenUCT DO - 10.1186/s12967-014-0230-1 DP - University of Cape Town J1 - Journal of Translational Medicine LK - https://open.uct.ac.za PB - University of Cape Town PY - 2014 T1 - Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma TI - Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma UR - http://hdl.handle.net/11427/13626 ER - en_ZA
dc.identifier.urihttp://hdl.handle.net/11427/13626
dc.identifier.urihttp://dx.doi.org/10.1186/s12967-014-0230-1
dc.identifier.vancouvercitationMelis M, Diaz G, Kleiner DE, Zamboni F, Kabat J, Lai J, et al. Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma. Journal of Translational Medicine. 2014; http://hdl.handle.net/11427/13626.en_ZA
dc.language.rfc3066en
dc.publisher.departmentDepartment of Medicineen_ZA
dc.publisher.facultyFaculty of Health Sciencesen_ZA
dc.publisher.institutionUniversity of Cape Town
dc.rightsThis is an Open Access article distributed under the terms of the Creative Commons Attribution License*
dc.rights.holderMelis et al.; licensee BioMed Central Ltd.
dc.rights.urihttp://creativecommons.org/licenses/by/4.0*
dc.sourceJournal of Translational Medicineen_ZA
dc.source.urihttp://www.translational-medicine.com/
dc.subject.otherHepatocellular carcinomaen_ZA
dc.subject.otherHepatitis B virusen_ZA
dc.subject.otherGene expression profilingen_ZA
dc.subject.otherLaser capture microdissectionen_ZA
dc.subject.otherConfocal microscopyen_ZA
dc.titleViral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma
dc.typeJournal Articleen_ZA
uct.type.filetype
uct.type.filetypeText
uct.type.filetypeImage
uct.type.publicationResearchen_ZA
uct.type.resourceArticleen_ZA
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