Interleukin-6 and oncostatin M are elevated in liver disease in conjunction with candidate hepatocellular carcinoma biomarker GP73

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.

Aberrant expression of p-STAT3 in peripheral blood CD4+ and CD8+ T cells related to hepatocellular carcinoma development

“…In addition, STAT3 is constitutively activated in HCC (23). The serum level of IL-6 was also found to be elevated in HCC, and a higher serum level of IL-6 was associated with HCC progression (37). Here, we found that IL-6 expression is increased and positively correlates to the p-STAT3 level in the serum of HCC patients and in the supernatant of co-cultured PBMCs and Huh7 cells.…”

Inter-individual variability and genetic influences on cytokine responses to bacteria and fungi

“…GOLM1 encodes a Golgi phosphoprotein, also referred as GP73, which is known to respond to viral infections 19 . This molecule has also been tested as a useful circulating biomarker for several viral and non-viral induced liver diseases 39,40 and the serum GOLM1 levels was shown to correlate with serum IL-6 levels in hepatocellular carcinoma 41 . The trans -regulatory network of GOLM1 that we describe here provides further insights into the understanding of the GOLM1-mediated cytokine regulation, not only in cancer but also for infectious diseases.…”

Oncostatin M induces IL-33 expression in liver endothelial cells in mice and expands ST2+CD4+lymphocytes

“…In the present study we found that AdOSM infection did not induce liver injury; however, OSM was capable of inducing IL-33 in liver endothelial cells. OSM was reported to enhance the antiviral response in the hepatoma cell line in vitro (22), and the level of OSM was raised in patients with hepatic cirrhosis (46) or with hepatocellular carcinoma (23). We also stimulated HMEC-1 by OSM, which increased the expression of IL-33 at 16 h and in a dosedependent manner.…”

“…OSM has an important role in various biological processes, including hematopoiesis, chemotaxis, inflammation, embryonic development, cell differentiation, and tissue repair (40). Elevated levels of OSM were observed in liver pathology in association with hepatocellular carcinoma in humans (23). OSM enhanced the antiviral properties of type I interferon in a hepatoma cell line of liver epithelial cells and modulated innate and adaptive immune responses in vitro (22).…”