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

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Journal of Translational Medicine

, 12:230

First Online: 21 August 2014Received: 20 June 2014Accepted: 11 August 2014DOI: 10.1186-s12967-014-0230-1

Cite this article as: Melis, M., Diaz, G., Kleiner, D.E. et al. J Transl Med 2014 12: 230. doi:10.1186-s12967-014-0230-1


BackgroundThe 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.

MethodsWe 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.

ResultsAnalysis 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.

ConclusionsIntegrated 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.

KeywordsHepatocellular carcinoma Hepatitis B virus Gene expression profiling Laser capture microdissection Confocal microscopy AbbreviationsHBVHepatitis B virus

HCCHepatocellular carcinoma

GEPGene expression profiling

WLTWhole liver tissue

LCMLaser capture microdissection

FDRFalse discovery rate

FCFold change

Electronic supplementary materialThe online version of this article doi:10.1186-s12967-014-0230-1 contains supplementary material, which is available to authorized users.

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Autor: Marta Melis - Giacomo Diaz - David E Kleiner - Fausto Zamboni - Juraj Kabat - Jinping Lai - Giulia Mogavero - Ashley Tice


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