Chemerin-156 reduces liver tumor growth in vivo but has no effect on liver cell proliferation and migration

Objective:

Chemerin is an adipokine that is not only expressed in white adipocytes but also in hepatocytes at high levels. Chemerin functions in the regulation of glucose and lipid homeostasis, inflammation, adipogenesis and tumor growth. After secretion prochemerin is processed into certain isoforms which can activate the receptors chemokine-like receptor 1 and G-protein-coupled receptor 1 to varying extent. The most active isoforms of chemerin in mice are Chem-156 and Chem-155. The respective human isoforms are Chem-157 and Chem-156. In an orthotopic mouse model of hepatocellular carcinoma (HCC) Chem-156 reduces tumor growth (doi: 10.1038/onc.2016.516). Whether Chem-156 has a similar activity in carcinogen induced liver tumors and whether this or further isoforms impair proliferation and migration of hepatic tumor cells has not been analyzed in detail.

Methods:

Two week old C3 H/HeNRj mice were injected with diethylnitrosmine (DEN) to induce HCC. After six months mice were infected with 1012 adenoassociated virus 8 (AAV8) particles to achieve a liver specific overexpression of Chem-156. Furthermore, to characterize the physiological function of chemerin in hepatocellular carcinoma Chem-157 and Chem-156 were overexpressed in the human hepatic cancer cell line HepG2 and the human stellate cell line LX-2. In addition, the murine Chem-156 and Chem-155 were overexpressed in the murine hepatoma cell line Hepa1 – 6. Migration of the cell lines was analyzed with scratch assays and proliferation levels were determined with measurement of cell numbers 24, 48 and 72h after transfection.

Results:

Serum chemerin levels tended to be higher in AAV8-Chem-156-injected mice, while hepatic chemerin protein was increased three times compared to the AAV8-control-injected mice. Thereby, hepatic tumor burden was reduced by about 30%. Interestingly, Chem-155 was the most abundant isoform in the liver while Chem-156 was only detected in two out of eight animals infected with Chem-156 producing AAV. This suggests that Chem-156 is processed to Chem-155 in the liver. However, Chem-156 and Chem-155 or its human analogs have no effect on cell proliferation in Hepa1 – 6 cells, the murine hepatic stellate cell line LX-2 or HepG2 cells. Furthermore, migration of Hepa1 – 6 cells is not influenced by these overexpressed chemerin isoforms.

Conclusions:

Chem-156 overexpression in the liver reduces hepatic tumor burden in the DEN-HCC model. Chem-156 seems to be converted to Chem-155 in the liver. However, both of these isoforms have no effect on cell proliferation or migration.