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.
Highlights
Hepatocellular carcinoma (HCC) is among the deadliest solid cancers, with the main etiologies being viral infections and non-alcoholic steatohepatitis (NASH) [1]
Based on experimental evidence indicating a role of myeloid cells in supporting tumor angiogenesis, metastasis, and progression, the dysregulated response of immune cells is believed to contribute to tumor growth in HCC [2,3]
The PC/PE ratio was similar in both groups, indicating that chemerin-156 overexpression did not modulate liver injury induced by DEN (Figure 3e)
Summary
Hepatocellular carcinoma (HCC) is among the deadliest solid cancers, with the main etiologies being viral infections and non-alcoholic steatohepatitis (NASH) [1]. Chemerin expression is low in adrenocortical carcinoma and chemerin overexpression in immune-deficient mice reduced tumor growth This was in line with demonstrated in vitro inhibitory effects on cell proliferation, invasion, and tumorigenicity [8]. The growth inhibitory activity of chemerin in a murine melanoma model is associated with an increased number of natural killer cells and the depletion of myeloid-derived suppressor cells and plasmacytoid dendritic cells [9] In contrast to these anti-cancer effects, neuroblastoma tumor growth is reportedly reduced when chemerin/CMKLR1 signaling is blocked [10]. Consistent with this, chemerin overexpression blocked aggressive tumor growth and metastasis in chemerin knock-out mice This was attributed to reduced activation of nuclear factor-κB, as well as the expression of granulocyte-macrophage colony-stimulating factor and IL-6. TotalScehruemmechreinmeprrinotweians mweaassuhriegdhiemrmaetdaialltetlhyebteifmoree apnodin1,ts4,fo8,r1c2h, eamnde1r3inw-1e5ek6s-AafAteVr -AinAfVected mice (Figure 2a)i.nCjechtieomn.eTrointalacchteivmietryininprsoeteriunmwaws haisghmereaatsualrletdheattimthe epoeinndts ofofrtchheemsteuridn-y1.56T-hAeAVex-invfeivctoedactivation of CMKLRm1iwcea(sFihguigreh2ear).inChcehmeemrineraicnti-v1it5y6i-ninsfeerucmtedwams imceea, swurhederaetatshetheendacotfivthaetisotundyo.fTGheperxovteivion-coupled activation of CMKLR1 was higher in chemerin-156-infected mice, whereas the activation of G proteinreceptor 1 (cGouPpRle1d)rebcyepsteorru1m(GPchR1e)mbyersienruwmacshenmoetrsinigwnaisfincoatnstiglyniifincadnutlcyeidnd(uFciegdu(rFeig2ubre,c2)b.,cH). eHpeaptaitcicchemerin protein wacshaemboeruint tpwroote-ifnolwdaisnacbroeuatsetwdoi-nfolcdhienmcreearsiend-1in56c-hAemAeVri-ni-n1f5e6c-AteAdVm-inifceecte(dFimguicree(F2idgu).reO2vde).rall, these data confirOmverraailsl,etdhehseedpaataticcopnfriormduracitsieodnheapnadticrperloedauscetioonf canhdemreleeraisne oinf cthoemtheerinciirnctuo ltahteiocinrc.ulation
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