Lin Y, Yang X, Liu W, Li B, Yin W, Shi Y, He R
Department of Immunology and Key Laboratory of Medical Molecular Virology of Ministries of Education and Health, School of Basic Medical Sciences, Shanghai, People's Republic of China.
Key Laboratory of Carcinogenesis and Cancer Invasion of Ministry of Education, Department of Liver Surgery, Liver Cancer Institute, Zhongshan Hospital, Shanghai, People's Republic of China.
Oncogene. 2017 Jun 22;36(25):3599-3608. doi: 10.1038/onc.2016.516. Epub 2017 Feb 6.
Hepatocellular carcinoma (HCC) is linked to inflammation and immunosuppression. Chemerin is highly expressed in the liver and implicated in the regulation of inflammation. However, the role of chemerin in HCC remains unclear. In this study, we aimed to investigate whether chemerin is able to influence HCC progression by regulating tumor-associated inflammation. Here we demonstrated that chemerin significantly decreased in blood and tumor tissues of HCC patients, and tumor chemerin levels were inversely associated with the prognosis. In an orthotopic mouse model of HCC, Rarres2 mice exhibited aggressive tumor growth and lung metastasis, whereas chemerin overexpression greatly inhibited tumor growth. The tumor-inhibitory effect of chemerin was accompanied by a shift in tumor-infiltrating immune cells from myeloid-derived suppressive cells (MDSCs) to interferon-γT cells and decreased tumor angiogenesis. Furthermore, we demonstrated that the tumor-inhibitory effect of chemerin was partly dependent on T cells, as chemerin overexpression could inhibit tumor growth, albeit to a lesser extent, in Rag1 mice when compared with wild-type controls. Mechanistically, chemerin inhibited nuclear factor-κB activation and the expression of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin-2 (IL-6) by tumor cells and tumor-associated endothelial cell, respectively, via its receptors, and consequently, MDSC induction was impaired, leading to restoration of antitumor T-cell response and decreased tumor angiogenesis. Clinically, systemic and tumor levels of chemerin were found to inversely correlate with circulating concentrations of GM-CSF or IL-6 and tumor-infiltrating myeloid cells, respectively, in HCC patients. Moreover, neutralization of GM-CSF and IL-6 abrogated HCC progression and MDSC accumulation in Rarres2 mice. In conclusion, our study reveals the tumor-inhibitory effect of chemerin by suppressing inflammatory tumor microenvironment with therapeutic implications for inflammation-associated cancer-like HCC.
肝细胞癌（HCC）与炎症和免疫抑制相关。趋化素在肝脏中高表达，并参与炎症调节。然而，趋化素在HCC中的作用仍不清楚。在本研究中，我们旨在探究趋化素是否能够通过调节肿瘤相关炎症来影响HCC进展。在此我们证明，HCC患者血液和肿瘤组织中的趋化素显著降低，且肿瘤趋化素水平与预后呈负相关。在HCC原位小鼠模型中，Rarres2小鼠表现出侵袭性肿瘤生长和肺转移，而趋化素过表达则极大地抑制了肿瘤生长。趋化素对肿瘤生长的抑制作用伴随着肿瘤浸润免疫细胞从髓系来源抑制细胞（MDSC）向干扰素-γ T细胞的转变，并减少了肿瘤血管生成。此外，我们证明趋化素的肿瘤抑制作用部分依赖于T细胞，因为与野生型对照相比，趋化素过表达在Rag1小鼠中虽能抑制肿瘤生长，但程度较轻。机制上，趋化素分别通过其受体抑制肿瘤细胞和肿瘤相关内皮细胞中核因子-κB的激活以及粒细胞-巨噬细胞集落刺激因子（GM-CSF）和白细胞介素-2（IL-6）的表达，因此，MDSC的诱导受损导致抗肿瘤T细胞反应恢复和肿瘤血管生成减少。临床上，在HCC患者中发现，趋化素的全身水平和肿瘤水平分别与GM-CSF或IL-6的循环浓度以及肿瘤浸润髓系细胞呈负相关。此外，中和GM-CSF和IL-6可消除Rarres2小鼠中的HCC进展和MDSC积累。总之，我们的研究揭示了趋化素通过抑制炎症性肿瘤微环境对HCC等炎症相关癌症具有治疗意义的肿瘤抑制作用。
