Abstract：
High levels of acetyl-CoA are considered a key metabolic feature of metastatic cancers. However, the impacts of acetyl-CoA metabolic accumulation on cancer microenvironment remodeling are poorly understood. In this study, using human hepatocellular carcinoma (HCC) tissues and orthotopic xenograft models, we found a close association between high acetyl-CoA levels in HCCs, increased infiltration of tumor-associated neutrophils (TANs) in the cancer microenvironment and HCC metastasis. Cytokine microarray and enzyme-linked immunosorbent assays (ELISA) revealed the crucial role of the chemokine (C-X-C motif) ligand 1(CXCL1). Mechanistically, acetyl-CoA accumulation induces H3 acetylation-dependent upregulation of CXCL1 gene expression. CXCL1 recruits TANs, leads to neutrophil extracellular traps (NETs) formation and promotes HCC metastasis. Collectively, our work linked the accumulation of acetyl-CoA in HCC cells and TANs infiltration, and revealed that the CXCL1-CXC receptor 2 (CXCR2)-TANs-NETs axis is a potential target for HCCs with high acetyl-CoA levels.
摘要：
高水平的乙酰辅酶A被认为是转移性癌症的关键代谢特征。然而,乙酰辅酶A代谢积累对癌症微环境重塑的影响知之甚少。在这项研究中,使用人类肝细胞癌（HCC）组织和原位异种移植模型，我们发现高乙酰辅酶A水平与肝癌细胞密切相关，肿瘤相关中性粒细胞（TANs）在肿瘤微环境中的浸润增加和HCC转移。细胞因子微阵列和酶联免疫吸附测定（ELISA）揭示了趋化因子（C-X-C基序）配体1（CXCL1）的关键作用。机械上,乙酰辅酶A积累诱导CXCL1基因表达的H3乙酰化依赖性上调。CXCL1招募TAN，导致中性粒细胞胞外陷阱（NETs）形成并促进HCC转移。总的来说，我们的工作将乙酰辅酶A在肝癌细胞中的积累与TANs浸润联系起来，并揭示CXCL1-CXC受体2（CXCR2）-TANs-NET轴是具有高乙酰辅酶A水平的HCC的潜在靶标。
