Circulating Survivin-IGM is a Novel Candidate Biomarker of Cirrhosis and Increases with Child Score in Patients Affected by Liver Diseases

Abstract

Background Survivin, also known as BIRC5, is the smallest member of the mammalian IAP family and is a well recognized inhibitor of apoptosis with an important role in cell-cycle regulation. It is detected in fetal and neoplastic adult tissue, but not in normal tissues. Survivin acts on cancer promotion not only by the inhibition of apoptosis but also by acceleration of the proliferative activity of cancer cells and several papers have suggested the involvement of this protein in hepatocarcino-genesis. It has been reported that the detection of HCC biomarkers circulating as IgM immune complexes (ICs) improved the diagnosis and prognosis of HCC. The aim of this study was to compare the expression of survivin as an IgM immune complex in serum from healthy controls and of patients with cirrhosis and patients with HCC to identify a novel biomarker for the monitoring of liver diseases. Methods Serum levels of survivin-IgM from 1 97 individuals, including 39 healthy subjects, 94 patients with cirrhosis and 64 with HCC, were measured by ELISA and the relationship with clinical parameters was evaluated. Results Survivin-IgM was almost undetectable in sera from healthy subjects, high in patients with cirrhosis, and moderately lower in patients with HCC. The survivin-IgM assay was positive in 62 of 94 patients with cirrhosis (66%) and in 28 of 64 patients with HCC (43.7%) using a cut-off of 264.89 AU/mL (specificity of 94%). Statistical analysis showed that IC values were significantly different between groups (cirrhosis versus healthy control group, p<0.001; HCC versus cirrhosis group, p<0.001). Circulating survivin-IgM ICs in patients with HCC were lower than in patients with cirrhosis; in fact, the statistical significance in comparison with healthy subjects was lost. On the other hand, the concentration of circulating survivin-IgM ICs was found to increase with progression of Child score. Conclusions The high expression of survivin-IgM in sera from patients with cirrhosis and the values of sensitivity indicate that survivin-IgM could be a novel candidate biomarker for cirrhotic disease. Furthermore, the increase in ICs with the progression of Child score seems to promote the survivin-IgM immune complex as marker of liver failure. Survivin-IgM was found to be lower in sera from HCC patients. Follow-up studies are in progress to monitor patients with cirrhosis and to validate the association of the downregulation of this marker with progression towards hepatocellular carcinoma.