Gene expression profiling unravels cancer-related hepatic molecular signatures in steatohepatitis but not in steatosis.
BACKGROUND
Pathogenesis and factors for determining progression of alcoholic and non-alcoholic steatosis to steatohepatitis with risk of further progression to liver cirrhosis and cancer are poorly understood. In the present study, we aimed to identify potential molecular signatures for discrimination of steatohepatitis from steatosis.


RESULTS
Global microarray gene expression analysis was applied to unravel differentially expressed genes between steatohepatitis compared to steatosis and control samples. For functional annotation as well as the identification of disease-relevant biological processes of the differentially expressed genes the gene ontology (GO) database was used. Selected candidate genes (n = 46) were validated in 87 human liver samples from two sample cohorts by quantitative real-time PCR (qRT-PCR). The GO analysis revealed that genes down-regulated in steatohepatitis were mainly involved in metabolic processes. Genes up-regulated in steatohepatitis samples were associated with cancer progression and proliferation. In surgical liver resection samples, 39 genes and in percutaneous liver biopsies, 30 genes were significantly up-regulated in steatohepatitis. Furthermore, immunohistochemical investigation of human liver tissue revealed a significant increase of AKR1B10 protein expression in steatohepatitis.


CONCLUSIONS
The development of steatohepatitis is characterized by distinct molecular changes. The most striking examples in this respect were KRT23 and AKR1B10, which we found to be highly differentially expressed in steatohepatitis compared to steatosis and normal liver. We propose that KRT23 and AKR1B10 may serve as future potential biomarkers for steatohepatitis as well as markers for progression to HCC.
Unit Cancer Genome Research, German Cancer Research Center and National Center for Tumor Diseases, Heidelberg, Germany.
Julia
J
Starmann
Maria
M
Fälth
Walter
W
Spindelböck
Katja-Lauren
KL
Lanz
Carolin
C
Lackner
Kurt
K
Zatloukal
Michael
M
Trauner
Holger
H
Sültmann
D000328:Adult; D000368:Aged; D000449:Aldehyde Reductase / Q000235:genetics / Q000378:metabolism; D000074408:Aldo-Keto Reductases; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D016000:Cluster Analysis; D005234:Fatty Liver / Q000378:metabolism*; D005260:Female; D019698:Hepatitis C, Chronic / Q000378:metabolism; D006801:Humans; D053530:Keratins, Type I / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D020411:Oligonucleotide Array Sequence Analysis; D025341:Principal Component Analysis; D059467:Transcriptome; D015854:Up-Regulation; D055815:Young Adult
D014408:Biomarkers, Tumor; C420247:KRT23 protein, human; D053530:Keratins, Type I; C120471:AKR1B10 protein, human; D000074408:Aldo-Keto Reductases; D000449:Aldehyde Reductase