Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma

Int J Mol Sci. 2019 Dec 30;21(1):252. doi: 10.3390/ijms21010252.

Abstract

The tumor inhibitory potential of the highly active chemerin-156 isoform was described in orthotopic models of hepatocellular carcinoma (HCC). The majority of HCC arises in the fibrotic liver, which was not reproduced in these studies. Here, a potential therapeutic activity of chemerin-156 was evaluated in diethylnitrosamine (DEN)-induced liver cancer, which mimics fibrosis-associated HCC. Mice were infected with adeno-associated virus (AAV) six months after DEN injection to overexpress chemerin-156 in the liver, and animals injected with non-recombinant-AAV served as controls. Three months later, the animals were killed. Both groups were comparable with regard to liver steatosis and fibrosis. Of note, the number of very small tumors was reduced by chemerin-156. Anyhow, the expression of inflammatory and profibrotic genes was similar in larger tumors of control and chemerin-156-AAV-infected animals. Although genes with a role in lipid metabolism, like 3-hydroxy-3-methylglutaryl-coenzym-A--reductase, were overexpressed in tumors of animals with high chemerin-156, total hepatic cholesterol, diacylglycerol and triglyceride levels, and distribution of individual lipid species were normal. Chemerin-156-AAV-infected mice had elevated hepatic and systemic chemerin. Ex vivo activation of the chemerin receptor chemokine-like receptor 1 increased in parallel with serum chemerin, illustrating the biological activity of the recombinant protein. In the tumors, chemerin-155 was the most abundant variant. Chemerin-156 was not detected in tumors of the controls and was hardly found in chemerin-156-AAV infected animals. In conclusion, the present study showed that chemerin-156 overexpression caused a decline in the number of small lesions but did not prevent the growth of pre-existing neoplasms.

Keywords: Triglycerides; adenoassociated virus; chemerin activity; chemokine-like receptor 1; liver.

MeSH terms

  • Animals
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / metabolism*
  • Carcinoma, Hepatocellular / pathology
  • Chemokines / blood
  • Chemokines / genetics
  • Chemokines / metabolism*
  • Cholesterol / metabolism
  • Diethylnitrosamine / adverse effects*
  • Diglycerides / metabolism
  • Disease Models, Animal
  • Gene Expression Regulation, Neoplastic
  • Hepatocytes / metabolism*
  • Intercellular Signaling Peptides and Proteins / blood
  • Intercellular Signaling Peptides and Proteins / genetics
  • Intercellular Signaling Peptides and Proteins / metabolism*
  • Lipid Metabolism
  • Liver / injuries
  • Liver / metabolism
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • Liver Neoplasms, Experimental / metabolism
  • Liver Neoplasms, Experimental / pathology
  • Male
  • Mice
  • Mice, Inbred C3H
  • Protein Isoforms
  • Receptors, Chemokine
  • Triglycerides / metabolism
  • Tumor Burden / physiology*

Substances

  • CMKLR1 protein, mouse
  • Chemokines
  • Diglycerides
  • Intercellular Signaling Peptides and Proteins
  • Protein Isoforms
  • Receptors, Chemokine
  • Triglycerides
  • chemerin protein, mouse
  • Diethylnitrosamine
  • Cholesterol