Serum microRNA-122 predicts survival in patients with liver cirrhosis

Background: Liver cirrhosis is associated with high morbidity and mortality. MicroRNAs (miRs) circulating in the blood are an emerging new class of biomarkers. In particular, the serum level of the liver-specific miR-122 might be a clinically useful new parameter in patients with acute or chronic liver disease. Aim: Here we investigated if the serum level of miR-122 might be a prognostic parameter in patients with liver cirrhosis. Methods: 107 patients with liver cirrhosis in the test cohort and 143 patients in the validation cohort were prospectively enrolled into the present study. RNA was extracted from the sera obtained at the time of study enrollment and the level of miR-122 was assessed. Serum miR-122 levels were assessed by quantitative reverse-transcription PCR (RT-PCR) and were compared to overall survival time and to different complications of liver cirrhosis. Results: Serum miR-122 levels were reduced in patients with hepatic decompensation in comparison to patients with compensated liver disease. Patients with ascites, spontaneous bacterial peritonitis and hepatorenal syndrome had significantly lower miR-122 levels than patients without these complications. Multivariate Cox regression analysis revealed that the miR-122 serum levels were associated with survival independently from the MELD score, sex and age. Conclusions: Serum miR-122 is a new independent marker for prediction of survival of patients with liver cirrhosis

Development of abiotic stress tolerance via bZIP-type transcription factor LIP19 in common wheat

BackgroundAutotaxin (ATX) and its product lysophosphatidic acid (LPA) are considered to be involved in the development of liver fibrosis and elevated levels of serum ATX have been found in patients with hepatitis C virus associated liver fibrosis. However, the clinical role of systemic ATX in the stages of liver cirrhosis was unknown. Here we investigated the relation of ATX serum levels and severity of cirrhosis as well as prognosis of cirrhotic patients.MethodsPatients with liver cirrhosis were prospectively enrolled and followed until death, liver transplantation or last contact. Blood samples drawn at the day of inclusion in the study were assessed for ATX content by an enzyme-linked immunosorbent assay. ATX levels were correlated with the stage as well as complications of cirrhosis. The prognostic value of ATX was investigated by uni- and multivariate Cox regression analyses. LPA concentration was determined by liquid chromatography-tandem mass spectrometry.Results270 patients were enrolled. Subjects with liver cirrhosis showed elevated serum levels of ATX as compared to healthy subjects (0.814±0.42 mg/l vs. 0.258±0.40 mg/l, PConclusionSerum ATX is an indicator for the severity of liver disease and the prognosis of cirrhotic patients

Serum miR-122 levels in the validation cohort and overall survival in the combined cohort.

<p>(<b>A</b>) Serum miR-122 in patients with and without hepatic decompensation. (<b>B</b>) miR-122 levels in patients with and without ascites. The vertical lines indicate the range, the horizontal boundaries of the boxes represent the first and third quartile. The analysis was performed with Kruskal-Wallis test and the Bonferroni correction was used for the sub-analysis. The number of patients in each group is indicated in the figure. (<b>C</b>) Survival curves for patients in the validation cohort with high or low serum miR-122 levels. The analysis was performed with the Cox regression model. (<b>D</b>) Survival curves for patients in the combined cohort with high or low serum miR-122 levels. The analysis was performed with the Cox regression model.</p

MicroRNA Profiling of Laser-Microdissected Hepatocellular Carcinoma Reveals an Oncogenic Phenotype of the Tumor Capsule

Several microRNAs (miRNAs) are associated with the molecular pathogenesis of hepatocellular carcinoma (HCC). However, previous studies analyzing the dysregulation of miRNAs in HCC show heterogeneous results. We hypothesized that part of this heterogeneity might be attributable to variations of miRNA expression deriving from the HCC capsule or the fibrotic septa within the peritumoral tissue used as controls. Tissue from surgically resected hepatitis C–associated HCC from six well-matched patients was microdissected using laser microdissection and pressure catapulting technique. Four distinct histologic compartments were isolated: tumor parenchyma (TP), fibrous capsule of the tumor (TC), tumor-adjacent liver parenchyma (LP), and cirrhotic septa of the tumor-adjacent liver (LC). MiRNA expression profiling analysis of 1105 mature miRNAs and precursors was performed using miRNA microarray. Principal component analysis and consecutive pairwise supervised comparisons demonstrated distinct patterns of expressed miRNAs not only for TP versus LP (e.g., intratumoral down-regulation of miR-214, miR-199a, miR-146a, and miR-125a; P< .05) but also for TC versus LC (including down-regulation within TC of miR-126, miR-99a/100, miR-26a, and miR-125b; P< .05). The tumor capsule therefore demonstrates a tumor-like phenotype with down-regulation of well-known tumor-suppressive miRNAs. Variations of co-analyzed fibrotic tissue within the tumor or in controls may have profound influence on miRNA expression analyses in HCC. Several miRNAs, which are proposed to be HCC specific, may indeed be rather associated to the tumor capsule. As miRNAs evolve to be important biomarkers in liver tumors, the presented data have important translational implications on diagnostics and treatment in patients with HCC

Patient characteristics.

<p>Abbreviations: ¹model of end stage liver disease, ²normal value: 135–145 mmol/l ³alanine aminotransferase (normal values: female: 10–35 U/l, male: 10–50 U/l), ⁴aspartate aminotransferase (normal values: female: <35 U/l, male: <40 U/l), ⁵γ-glutamyltransferase (normal values: female: <40 U/l, male: <60 U/l), ⁶alkaline phosphatase (normal values: female: 55–105 U/l, male: 40–130 U/l), ⁷normal values: 3.5–5.2 mg/dl, ⁸normal values: <1 mg/dl, ⁹international normalized ratio, ¹⁰normal values: female: 0.5–0.9 mg/dl, male: 0.7–1.2 mg/dl.</p

Correlation between miR-122 serum levels and laboratory parameters.

<p>Abbreviation: ¹Model of end stage liver disease.</p

Serum miR-122 levels in cirrhotic patients with and without hepatic decompensation.

<p>The vertical lines indicate the range, the horizontal boundaries of the boxes represent the first and third quartile. The number of patients in each group is indicated in the figure.</p

Univariate and multivariate analysis of parameters associated with overall survival.

<p>Abbreviations:</p><p>HR, hazard ratio; CI, confidence interval; MELD, model of end stage liver disease.</p

Serum miR-122 levels in complications of liver cirrhosis.

<p>The vertical lines indicate the range, the horizontal boundaries of the boxes represent the first and third quartile. The number of patients in each group is indicated in the figure.</p

Serum miR-122 levels are associated with survival in patients with liver cirrhosis.

<p>(<b>A</b>) Distribution of serum miR-122 levels throughout the patients. The cut-off value for the patient cohorts is marked in blue. (<b>B</b>) Survival curves for patients with high or low serum miR-122 levels. The analysis was performed with the Cox regression model.</p