Serum MicroRNA-21 as Marker for Necroinflammation in Hepatitis C Patients with and without Hepatocellular Carcinoma

Abstract

BackgroundMicroRNA-21 (miR-21) is up-regulated in tumor tissue of patients with malignant diseases, including hepatocellular carcinoma (HCC). Elevated concentrations of miR-21 have also been found in sera or plasma from patients with malignancies, rendering it an interesting candidate as serum/plasma marker for malignancies. Here we correlated serum miR-21 levels with clinical parameters in patients with different stages of chronic hepatitis C virus infection (CHC) and CHC-associated HCC.Methodology/Principal Findings62 CHC patients, 29 patients with CHC and HCC and 19 healthy controls were prospectively enrolled. RNA was extracted from the sera and miR-21 as well as miR-16 levels were analyzed by quantitative real-time PCR; miR-21 levels (normalized by miR-16) were correlated with standard liver parameters, histological grading and staging of CHC. The data show that serum levels of miR-21 were elevated in patients with CHC compared to healthy controls (P<0.001); there was no difference between serum miR-21 in patients with CHC and CHC-associated HCC. Serum miR-21 levels correlated with histological activity index (HAI) in the liver (r = −0.494, P = 0.00002), alanine aminotransferase (ALT) (r = −0.309, P = 0.007), aspartate aminotransferase (r = −0.495, P = 0.000007), bilirubin (r = −0.362, P = 0.002), international normalized ratio (r = −0.338, P = 0.034) and γ-glutamyltransferase (r = −0.244, P = 0.034). Multivariate analysis revealed that ALT and miR-21 serum levels were independently associated with HAI. At a cut-off dCT of 1.96, miR-21 discriminated between minimal and mild-severe necroinflammation (AUC = 0.758) with a sensitivity of 53.3% and a specificity of 95.2%.Conclusions/SignificanceThe serum miR-21 level is a marker for necroinflammatory activity, but does not differ between patients with HCV and HCV-induced HCC.

The Role of Circulating MicroRNAs as Markers of Disease Progression in Hepatitis C Virus Infected Egyptian Patients

“…Our miRNA-21 results are not matching with many other studies that report an up-regulation of miRNA-21 in many cancers including HCC [14]- [19]. Bihrer et al [20] demonstrated that the level of miRNA-21 in sera from patients with chronic hepatitis C associated HCC was elevated compared to healthy controls. But they also detected increased levels of miRNA-21 in sera from patients with chronic hepatitis C without HCC, suggesting that this elevation of serum miRNA-21 levels appears to be mainly associated with chronic hepatitis rather than HCC.…”

HepatomiRNoma: The proposal of a new network of targets for diagnosis, prognosis and therapy in hepatocellular carcinoma

“…This miRNA is the first to be studied as a therapeutic tool and other two studies (Connolly et al, 2008;Zhu et al, 2011) have shown that the transfection of tumor cells with antisense oligonucleotides specific for mir-21 leads to a reduction of the cell growth and survival. Likewise studies by Xu et al (2011a), Bihrer et al (2011), Marquez et al (2010 have shown that serum levels of miR-21 are increased with a progressive course from chronic hepatitis to cirrhosis and hepatocellular carcinoma. Multivariate analyses demonstrate that the only parameters to be associated with this miRNA are histological necroinflammation and viral load.…”

Dysregulation of global microRNA expression in splenic marginal zone lymphoma and influence of chronic hepatitis C virus infection

“…Different serum-miRNAs were found to correlate with liver inflammation and fibrosis indirectly caused by the virus. 46,47 Various studies reported on miRNA expression in hepatocellular carcinoma tissue of HCV-positive patients, but again these findings are likely not exclusively caused by HCV infection but rather by the tumor itself or again by HCV-induced liver damage. 7,48,49 The diminished expression of miR-26b, as seen in the HCV-positive lymphoma group, has been linked to a malignant tumor phenotype in hepatocellular carcinoma 50 and lung carcinoma 51 as well as in cell culture models of colon cancer and diffuse large B-cell lymphoma.…”