Gene Expression Profiling Unravels Cancer-Related Hepatic Molecular Signatures in Steatohepatitis but Not in Steatosis

Abstract

BackgroundPathogenesis 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.Methodology and ResultsGlobal 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.ConclusionsThe 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.

From Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: A Systems Understanding

“…Another gene expression profiling study reported that cancer-related molecular signatures are associated with NASH but not with steatosis [9]. Although the sample size of this study (10 NASH, 30 steatosis, 18 controls) was similar to that of Clarke et al [1], the steatohepatitis group included alcoholic and non-alcoholic subgroups sharing similar hepatic morphology.…”

“…Unsupervised clustering divided samples into steatosis and NASH groups, with only metabolic processes upregulated in steatosis, whereas in NASH, upregulation of the cancer progression-associated pathways such as those regulating extracellular matrix organization were present. Two of the most differentially expressed genes in NASH were aldose reductase AKR1B10 and a keratin family member KRT23 that were identified previously as marker candidates in the progression of steatohepatitis to HCC [9].…”

“…A meta-analysis of both studies [1,9] would likely augment understanding of the pathways linking NASH with HCC. It would also likely help fill the current gaps between conclusions derived from small-scale gene expression profiling studies and large-scale analysis of SNPs (single nucleotide polymorphisms) or GWAS.…”

“…can add confusion and interpretational variability. Short of performing a new meta-analysis based on publically available datasets, it is not easy to conclude whether the hepatic genes that were identified in the two discussed gene expression profiling studies [1,9] are congruent with SNPs associated with HCC [10]. Although the gene clusters associated with oxidative stress, iron metabolism, inflammatory and immune response, DNA repair, and cell cycle regulation pathways are considered the most likely to be involved in the progression to HCC, the contribution of individual genes to this sequence is not conclusive.…”

Nem alkoholos zsírmáj és hepatocellularis carcinoma – 2016

“…Két praemalignus biomarker, a keraten multigén család tagja (KRT23) és az aldolázreduktáz (AKR1B10) gén upregulációja a steatosisból való korai NASH-és HCC-progresszióban ját-szik szerepet [27].…”