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

 

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dc.contributor.author Melis, Marta
dc.contributor.author Diaz, Giacomo
dc.contributor.author Kleiner, David E
dc.contributor.author Zamboni, Fausto
dc.contributor.author Kabat, Juraj
dc.contributor.author Lai, Jinping
dc.contributor.author Mogavero, Giulia
dc.contributor.author Tice, Ashley
dc.contributor.author Engle, Ronald E
dc.contributor.author Becker, Steven
dc.contributor.author Brown, Charles R
dc.contributor.author Hanson, Jeffrey C
dc.contributor.author Rodriguez-Canales, Jaime
dc.contributor.author Emmert-Buck, Michael
dc.contributor.author Govindarajan, Sugantha
dc.contributor.author Kew, Michael
dc.contributor.author Farci, Patrizia
dc.date.accessioned 2015-07-30T04:10:40Z
dc.date.available 2015-07-30T04:10:40Z
dc.date.issued 2014-08-21
dc.identifier.citation Melis, 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.uri http://hdl.handle.net/11427/13626
dc.identifier.uri http://dx.doi.org/10.1186/s12967-014-0230-1
dc.description.abstract 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.
dc.rights This is an Open Access article distributed under the terms of the Creative Commons Attribution License *
dc.rights.uri http://creativecommons.org/licenses/by/4.0 *
dc.source Journal of Translational Medicine en_ZA
dc.source.uri http://www.translational-medicine.com/
dc.subject.other Hepatocellular carcinoma en_ZA
dc.subject.other Hepatitis B virus en_ZA
dc.subject.other Gene expression profiling en_ZA
dc.subject.other Laser capture microdissection en_ZA
dc.subject.other Confocal microscopy en_ZA
dc.title Viral expression and molecular profiling in liver tissue versus microdissected hepatocytes in hepatitis B virus - associated hepatocellular carcinoma
dc.type Journal Article en_ZA
dc.date.updated 2015-01-15T17:58:45Z
dc.language.rfc3066 en
dc.rights.holder Melis et al.; licensee BioMed Central Ltd.
uct.type.publication Research en_ZA
uct.type.resource Article en_ZA
dc.publisher.institution University of Cape Town
dc.publisher.faculty Faculty of Health Sciences en_ZA
dc.publisher.department Department of Medicine en_ZA
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uct.type.filetype Text
uct.type.filetype Image


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This is an Open Access article distributed under the terms of the Creative Commons Attribution License Except where otherwise noted, this item's license is described as This is an Open Access article distributed under the terms of the Creative Commons Attribution License