Chemerin has a protective role in hepatocellular carcinoma by inhibiting the expression of IL-6 and GM-CSF and MDSC accumulation.
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-γ+T 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.
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.
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Lin
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.
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Yang
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.
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Liu
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.
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Li
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.
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Yin
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.
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Shi
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.|Department of Immunology, Biotherapy Research Center, Fudan University, Shanghai, People's Republic of China.
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0000-0001-5288-9786
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He
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018925:Chemokines / Q000235:genetics / Q000276:immunology*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics / Q000276:immunology*; D064593:Heterografts; D018398:Homeodomain Proteins / Q000235:genetics / Q000276:immunology; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology*; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology* / Q000473:pathology; D016328:NF-kappa B; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology*; D009368:Neoplasm Transplantation; D059016:Tumor Microenvironment
D018925:Chemokines; D018398:Homeodomain Proteins; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; D016328:NF-kappa B; D009363:Neoplasm Proteins; C478630:RARRES2 protein, human; C523686:chemerin protein, mouse; C064658:RAG-1 protein; D016178:Granulocyte-Macrophage Colony-Stimulating Factor