Affiliations: [a] Department of Microbiology and Immunology, Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, Doylestown, PA, USA | [b] Immunotope, Inc., Doylestown, PA, USA | [c] Division of Gastroenterology, University of Michigan, Ann Arbor, MI, USA | [d] Division of Clinical Hepatology, Department of Clinical Medicine and Center for Hepatobiliary Disease and Abdominal Transplantation, UCSD Medical Center, San Diego, CA, USA
Correspondence:
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Corresponding author: Pamela A. Norton, Ph.D., Drexel Institute for Biotechnology and Virology Research, Drexel University College of Medicine, 3805 Old Easton Road, Doylestown, PA 18902, USA. Tel.: +1 215 489 4903; Fax: +1 215 489 4920; E-mail: [email protected].
Abstract: The Golgi phosphoprotein GP73 is elevated in the circulation of individuals with a diagnosis of hepatocellular carcinoma. Its usefulness as a biomarker of HCC is questioned, since it has also been reported to be elevated in the circulation of people with liver cirrhosis. Regulation of GP73 by inflammatory cytokines is therefore of interest. The interleukin-6 (IL-6) family cytokines were tested for effects on GP73 mRNA and/or protein levels in human hepatoblastoma HepG2 cells. Levels of GP73 mRNA and protein were up-regulated in HepG2 cells following treatment with either proinflammatory cytokine IL-6 or the related cytokine oncostatin M (OSM). Induction required the shared receptor subunit gp130, and correlated with increased tyrosine phosphorylation of STAT3. Maximal cytokine-mediated induction was not observed in the presence of protein synthesis inhibitor cycloheximide, suggesting additional regulatory factors play an important role. ELISA measurement of GP73 and IL-6 levels in the sera of patients with pre-malignant liver disease revealed a significant correlation between circulating levels of the two proteins. Similarly, a sensitive ELISA assay was developed to measure circulating OSM. OSM levels were elevated 6–7 fold in sera from patients with either cirrhosis or HCC relative to controls without liver disease. Although there was an association between levels of GP73 and OSM in serum from people with liver cirrhosis, there was not a statistically significant correlation in HCC, suggesting that the role of the cytokines in determining circulating levels may be complex. To our knowledge, this is the first report of OSM elevation being associated with liver disease.
