FAST TRACK Progressive increase of SCCA-IgM immune complexes in cirrhotic patients is associated with development of hepatocellular carcinoma

Background: Epidemiological studies indicate that a growing number of cirrhotic patients will develop hepatocellular carcinoma (HCC) in the next decade. Recent findings have demonstrated that Squamous cell carcinoma antigen 1 (SCCA1) and 2 (SCCA2) isoforms, now classified as serpinB3 and serpinB4, are over-expressed in HCC, but not in normal liver. As reported, high levels of circulating SCCA-IgM immunocomplexes in patients with cirrhosis are significantly associated with HCC development. Aim: To ascertain whether IgM-linked SCCA isoforms circulate in patients with chronic liver disease, compared to total SCCA-IgM levels. Methodology and Findings: 79 patients with chronic liver disease were studied, including 17 patients with chronic hepatitis, 36 patients with cirrhosis and 26 with HCC. 28 blood donors were used as control. Monoclonal antibodies against serpinB3 and serpinB4 were used as catcher antibodies to set up specific ELISA assays, while total SCCA-IgM immunocomplexes were detected by commercially available ELISA assay. Overall, the results revealed a better diagnostic sensitivity of total SCCA-IgM assay, compared to both serpinB3 and serpinB4 IgM-linked assays. SerpinB4-IgM median values obtained with SCC103 antibody were moderately higher in patients with cirrhosis than in those with HCC, median values: 0.168 (IQR 0.140–0.427) vs. 0.140 (IQR 0.140–0.278), (p = 0.177). A trend toward decreasing serpinB4-IgM/serpinB3-IgM median ratio was observed in patients with advanced liver disease, being 1.08 in patients with HCC, 1.10 in patients with cirrhosis and 1.40 in patients with chronic hepatitis (p = 0.079). Conclusions: IgM-linked SCCA isoforms in serum of patients with chronic liver diseases were quantified for the first time. Although the number of patients was limited, this preliminary study reveals that the relative balance of the two serpin isoforms is altered in HCC and it is characterized by a lower serpinB4-IgM/serpinB3-IgM ratio, determined by lower serpinB4 levels. Citation: Biasiolo A, Tono N, Ruvoletto M, Quarta S, Turato C, et al. (2012) IgM-Linked SerpinB3 and SerpinB4 in Sera of Patients with Chronic Liver Disease. PLoS ONE 7(7): e40658. doi:10.1371/journal.pone. 0040658 Editor: Henrik Einwaechter, Klinikum rechts der Isar der TU München, Germany Received January 18, 2012; Accepted June 11, 2012; Published July 13, 2012 Copyright: 2012 Biasiolo et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work is supported in part by a grant from the National Ministry of Education, University and Research (FIRB Project Prot. RBLA03S4SP_005) and by a research grant from the Associazione Italiana per la Ricerca sul Cancro (AIRC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No additional external funding was received for this study. Competing Interests: The authors have read the journal’s policy and have the following conflicts of interest to declare: LB and GF are employees of Xeptagen S.p.A. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials. * E-mail: patrizia@unipd.it