BACKGROUND The activation of tumour-associated macrophages (TAMs) contributes to the progression of hepatocellular carcinoma (HCC). SIRT4 acts as a tumour suppressor of tumour growth by regulating cell metabolism, inflammation, and anti-tumourigenesis. However, the involvement of SIRT4 in the activation of TAMs is unknown. Based on previous findings, the expression of SIRT4 in distinct groups of TAMs as well as the effect of SIRT4 silencing on macrophage polarization was investigated. METHODS The expression of SIRT4 in HCC tissues and peritumour tissues was tested by qRT-PCR, western blotting and histological analysis. A Kaplan-Meier survival curve was generated based on the expression of SIRT4 in the HCC samples. Next, immunofluorescence staining was used to evaluate distinct groups of TAMs in human HCC samples, and the expression of SIRT4 in M1 and M2 TAMs was examined by flow cytometry. A homograft mouse model was used to assess the effect of SIRT4 silencing in TAMs on the development of HCC cells. RESULTS SIRT4 was significantly downregulated in HCC tumour tissues, and the expression of SIRT4 in peritumour tissues was positively associated with survival in patients. We further found that downregulation of SIRT4 was associated with increased macrophage infiltration and a high ratio of M2/M1 macrophages in HCC peritumour tissues. Using gene interference, we found that SIRT4 silencing in TAMs significantly modulated the alternative activation of macrophages and promoted in vitro and in vivo HCC cell growth. Mechanistically, we revealed that HCM restricted the expression of SIRT4 in macrophages and promoted alternative activation of macrophages via the FAO-PPARδ-STAT3 axis. Furthermore, we also revealed that elevated MCP-1 expression induced by SIRT4 downregulation was responsible for increased TAM infiltration in peritumour tissues. CONCLUSIONS Overall, our results demonstrate that downregulation of SIRT4 in TAMs modulates the alternative activation of macrophages and promotes HCC development via the FAO-PPARδ-STAT3 axis. These results could provide a new therapeutic target for the treatment of HCC.

中文翻译：

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肿瘤相关巨噬细胞中的SIRT4沉默通过PPARδ信号介导的巨噬细胞替代激活促进HCC的发展。

背景技术与肿瘤相关的巨噬细胞（TAM）的激活有助于肝细胞癌（HCC）的进展。SIRT4通过调节细胞代谢，炎症和抗肿瘤发生而充当肿瘤生长的肿瘤抑制因子。但是，SIRT4参与TAM激活尚不清楚。基于以前的发现，研究了SIRT4在不同TAM组中的表达以及SIRT4沉默对巨噬细胞极化的影响。方法采用qRT-PCR，Western blotting和组织学分析检测SIRT4在肝癌组织和癌旁组织中的表达。基于HCC样品中SIRT4的表达生成了Kaplan-Meier生存曲线。接下来，使用免疫荧光染色评估人类HCC样品中不同的TAM组，通过流式细胞术检测SIRT4在M1和M2 TAM中的表达。使用同种移植小鼠模型评估TAM中SIRT4沉默对HCC细胞发育的影响。结果SIRT4在肝癌组织中显着下调，SIRT4在肿瘤周围组织中的表达与患者的生存呈正相关。我们进一步发现SIRT4的下调与HCC肿瘤周围组织中巨噬细胞浸润增加和M2 / M1巨噬细胞比例升高有关。利用基因干扰，我们发现TAM中的SIRT4沉默显着调节了巨噬细胞的替代激活并促进了体外和体内HCC细胞的生长。机械上，我们发现，HCM限制了SIRT4在巨噬细胞中的表达，并通过FAO-PPARδ-STAT3轴促进了巨噬细胞的选择性激活。此外，我们还揭示了SIRT4下调诱导的MCP-1表达升高是肿瘤周围组织中TAM浸润增加的原因。结论总体而言，我们的结果表明，TAMs中SIRT4的下调可调节巨噬细胞的选择性激活，并通过FAO-PPARδ-STAT3轴促进肝癌的发展。这些结果可为肝癌的治疗提供新的治疗靶点。我们的结果表明，TAM中SIRT4的下调可调节巨噬细胞的选择性激活，并通过FAO-PPARδ-STAT3轴促进肝癌的发展。这些结果可为肝癌的治疗提供新的治疗靶点。我们的结果表明，TAM中SIRT4的下调可调节巨噬细胞的选择性激活，并通过FAO-PPARδ-STAT3轴促进肝癌的发展。这些结果可为肝癌的治疗提供新的治疗靶点。