Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma
Overexpression of Hepatocyte Chemerin-156 Lowers Tumor Burden in a Murine Model of Diethylnitrosamine-Induced Hepatocellular Carcinoma
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DOI：
10.3390/ijms21010252
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发表时间：
2020-01-01
影响因子：
5.6
通讯作者：
Buechler, Christa
中科院分区：
文献类型：
--
作者：
Haberl, Elisabeth M.;Pohl, Rebekka;Buechler, Christa
在肝细胞癌（HCC）原位模型中描述了高活性chemerin-156同种型的肿瘤抑制潜力。大多数HCC发生在纤维化肝脏中，这在这些研究中没有重现。在这里，chemerin-156的潜在治疗活性在二乙基亚硝胺（DEN）诱导的肝癌中进行了评估，该肝癌模拟纤维化相关的HCC。在DEN注射后6个月用腺相关病毒（AAV）感染小鼠以在肝脏中过表达chemerin-156，并且用非重组AAV注射的动物作为对照。三个月后，这些动物被杀了。两组在肝脏脂肪变性和纤维化方面具有可比性。值得注意的是，chemerin-156减少了非常小的肿瘤的数量。无论如何，炎症和促纤维化基因的表达在对照和chemerin-156-AAV感染的动物的较大肿瘤中相似。虽然基因在脂质代谢中的作用，如3-羟基-3-甲基戊二酰辅酶-A--还原酶，过度表达的动物肿瘤与高chemerin-156，总肝胆固醇，甘油二酯和甘油三酯水平，和个别脂质种类的分布是正常的。Chemerin-156-AAV感染的小鼠具有升高的肝脏和全身Chemerin。趋化因子受体趋化因子样受体1的离体活化与血清趋化因子平行增加，说明重组蛋白的生物活性。在肿瘤中，chemerin-155是最丰富的变体。在对照的肿瘤中未检测到Chemerin-156，并且在Chemerin-156-AAV感染的动物中几乎未发现Chemerin-156。总之，本研究表明，chemerin-156过表达引起小病变数量的下降，但不能阻止预先存在的肿瘤的生长。
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.