Abstract
Background and AimsMicro-RNAs (miRNAs) have recently emerged as crucial modulators of molecular processes involved in chronic liver diseases. The few miRNAs with previously proposed roles in liver cirrhosis were identified in screening approaches on liver parenchyma, mostly in rodent models. Therefore, in the present study we performed a systematic screening approach in order to identify miRNAs with altered levels in the serum of patients with chronic liver disease and liver cirrhosis.MethodsWe performed a systematic, array-based miRNA expression analysis on serum samples from patients with liver cirrhosis. In functional experiments we evaluated the relationship between alterations of miRNA serum levels and their role in distinct cellular compartments involved in hepatic cirrhosis.ResultsThe array analysis and the subsequent confirmation by qPCR in a larger patient cohort identified significant alterations in serum levels of miR-513-3p, miR-571 and miR-652, three previously uncharacterized miRNAs, in patients with alcoholic or hepatitis C induced liver cirrhosis. Of these, miR-571 serum levels closely correlated with disease stages, thus revealing potential as a novel biomarker for hepatic cirrhosis. Further analysis revealed that up-regulation of miR-571 in serum reflected a concordant regulation in cirrhotic liver tissue. In isolated primary human liver cells, miR-571 was up-regulated in human hepatocytes and hepatic stellate cells in response to the pro-fibrogenic cytokine TGF-β. In contrast, alterations in serum levels of miR-652 were stage-independent, reflecting a concordant down-regulation of this miRNA in circulating monocytes of patients with liver cirrhosis, which was inducible by proinflammatory stimuli like bacterial lipopolysaccharide.ConclusionAlterations of miR571 and miR-652 serum levels in patients with chronic liver disease reflect their putative roles in the mediation of fibrogenic and inflammatory processes in distinct cellular compartments involved in the pathogenesis of liver cirrhosis.
Highlights
Many chronic liver diseases are still not sufficiently treatable and often progress to liver cirrhosis representing the major risk factor for the development of hepatocellular carcinoma (HCC) [1]
Despite the potential of these findings for the establishment of novel biomarkers, serum-level alterations of miRNAs might reflect important regulatory processes occurring in distinct cellular compartments involved in disease pathogenesis. In line with this hypothesis, we recently demonstrated that the functional role of miR-29 in liver fibrosis correlated with a significant decrease of miR-29 serum levels [10]
The screening cohort consisted of four age- and sex-matched patients with histologically and clinically confirmed compensated alcoholic liver cirrhosis (Child-Pugh class A), four patients with decompensated alcoholic cirrhosis (Child-Pugh class C), four patients with compensated hepatitis C-related cirrhosis (ChildPugh class A) and four healthy volunteers as controls (Data S1)
Summary
Many chronic liver diseases are still not sufficiently treatable and often progress to liver cirrhosis representing the major risk factor for the development of hepatocellular carcinoma (HCC) [1]. Systematic array approaches on liver tissue from mice and primary hepatic stellate cells (HSCs) recently revealed important functional roles of certain miRNAs in hepatic fibrogenesis. It was shown that members of the miR-29 family integrate pro-fibrogenic and proinflammatory signals in hepatic stellate cells and control expression of various extracellular matrix genes during hepatic fibrogenesis [10,11,12]. Micro-RNAs (miRNAs) have recently emerged as crucial modulators of molecular processes involved in chronic liver diseases. The few miRNAs with previously proposed roles in liver cirrhosis were identified in screening approaches on liver parenchyma, mostly in rodent models. In the present study we performed a systematic screening approach in order to identify miRNAs with altered levels in the serum of patients with chronic liver disease and liver cirrhosis
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