Accumulating evidence indicates that ceramide (Cer) and palmitic acid (PA) possess the ability to modulate switching of macrophage phenotypes and possess anti-tumorigenic effects; however, the underlying molecular mechanisms are largely unknown. The aim of the present study was to investigate whether Cer and PA could induce switching of macrophage polarization from the tumorigenic M2- towards the pro-inflammatory M1-phenotype, and whether this consequently altered the potential of colorectal cancer cells to undergo epithelial-mesenchymal transition (EMT), a hallmark of tumor progression. Our study showed that Cer- and PA-treated macrophages increased expression of the macrophage 1 (M1)-marker CD68 and secretion of IL-12 and attenuated expression of the macrophage 2 (M2)-marker CD163 and IL-10 secretion. Moreover, Cer and PA abolished M2 macrophage-induced EMT and migration of colorectal cancer cells. At the molecular level, this coincided with inhibition of SNAI1 and vimentin expression and upregulation of E-cadherin. Furthermore, Cer and PA attenuated expression levels of IL-10 in colorectal cancer cells co-cultured with M2 macrophages and downregulated STAT3 and NF-κB expression. For the first time, our findings suggest the presence of an IL-10-STAT3-NF-κB signaling axis in colorectal cancer cells co-cultured with M2 macrophages, mimicking the tumor microenvironment. Importantly, PA and Cer were powerful inhibitors of this signaling axis and, consequently, EMT of colorectal cancer cells. These results contribute to our understanding of the immunological mechanisms that underlie the anti-tumorigenic effects of lipids for future combination with drugs in the therapy of colorectal carcinoma.

中文翻译：

---

神经酰胺和棕榈酸抑制结肠直肠癌中巨噬细胞介导的上皮-间质转化。

越来越多的证据表明，神经酰胺（Cer）和棕榈酸（PA）具有调节巨噬细胞表型转换的能力，并具有抗肿瘤作用。然而，基本的分子机制尚不清楚。本研究的目的是研究Cer和PA是否可以诱导巨噬细胞极化从致瘤M2-型向促炎性M1-表型转变，以及这是否因此改变了结直肠癌细胞发生上皮-间质转化的可能性（EMT），这是肿瘤进展的标志。我们的研究表明，经Cer和PA处理的巨噬细胞可增加巨噬细胞1（M1）标记CD68的表达和IL-12的分泌，并减弱巨噬细胞2（M2）标记CD163和IL-10的表达。此外，Cer和PA废除了M2巨噬细胞诱导的EMT和结直肠癌细胞的迁移。在分子水平上，这与抑制SNAI1和波形蛋白的表达以及上调E-钙黏着蛋白相吻合。此外，Cer和PA减弱了与M2巨噬细胞共培养的结直肠癌细胞中IL-10的表达水平，并下调了STAT3和NF-κB的表达。我们的发现首次表明，在与M2巨噬细胞共培养的大肠癌细胞中存在IL-10-STAT3-NF-κB信号转导轴，模拟了肿瘤的微​​环境。重要的是，PA和Cer是该信号轴的强力抑制剂，因此是结直肠癌细胞的EMT。