Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.
Deregulation of PPARβ/δ target genes in tumor-associated macrophages by fatty acid ligands in the ovarian cancer microenvironment.
复制标题
DOI：
10.18632/oncotarget.3826
复制
发表时间：
2015-05-30
期刊：
影响因子：
--
通讯作者：
Müller R
中科院分区：
文献类型：
--
作者：
Schumann T;Adhikary T;Wortmann A;Finkernagel F;Lieber S;Schnitzer E;Legrand N;Schober Y;Nockher WA;Toth PM;Diederich WE;Nist A;Stiewe T;Wagner U;Reinartz S;Müller-Brüsselbach S;Müller R
核受体过氧化物酶体增殖物激活受体β/δ（peroxisome proliferator-activated receptor β/δ，PPARβ/δ）是一种与巨噬细胞极化相关的脂质配体诱导型转录因子。然而，其在肿瘤相关巨噬细胞（TAM）中的功能迄今尚未研究。在这里，我们报告了卵巢癌患者TAMs的PPARβ/δ调节转录组和顺式异构体。与单核细胞衍生的巨噬细胞的比较表明，绝大多数直接的PPARβ/δ靶基因在TAM中上调，并且在很大程度上对合成激动剂不敏感，但可被反向激动剂抑制。除了具有代谢功能的基因，这些基因还包括与免疫调节和肿瘤进展相关的细胞类型选择性基因，例如，LRP 5、CD 300 A、MAP 3K8和ANGPTL4。这种失调不是由于PPARβ/δ表达增加或其向靶基因的募集增强所致。相反，恶性肿瘤相关腹水的脂质组学分析显示高浓度的多不饱和脂肪酸，特别是亚油酸，在巨噬细胞中作为有效的PPARβ/δ激动剂。这些脂肪酸配体在TAM的脂滴中积累，从而提供了PPARβ/δ配体的储库。这些观察结果表明，肿瘤微环境配体对PPARβ/δ靶基因的失调有助于卵巢癌TAM的促肿瘤发生极化。这一结论得到了ANGPTL 4高表达与浆液性卵巢癌较短无复发生存期相关性的支持。
The nuclear receptor peroxisome proliferator-activated receptor β/δ (PPARβ/δ) is a lipid ligand-inducible transcription factor associated with macrophage polarization. However, its function in tumor-associated macrophages (TAMs) has not been investigated to date. Here, we report the PPARβ/δ-regulated transcriptome and cistrome for TAMs from ovarian carcinoma patients. Comparison with monocyte-derived macrophages shows that the vast majority of direct PPARβ/δ target genes are upregulated in TAMs and largely refractory to synthetic agonists, but repressible by inverse agonists. Besides genes with metabolic functions, these include cell type-selective genes associated with immune regulation and tumor progression, e.g., LRP5, CD300A, MAP3K8 and ANGPTL4. This deregulation is not due to increased expression of PPARβ/δ or its enhanced recruitment to target genes. Instead, lipidomic analysis of malignancy-associated ascites revealed high concentrations of polyunsaturated fatty acids, in particular linoleic acid, acting as potent PPARβ/δ agonists in macrophages. These fatty acid ligands accumulate in lipid droplets in TAMs, thereby providing a reservoir of PPARβ/δ ligands. These observations suggest that the deregulation of PPARβ/δ target genes by ligands of the tumor microenvironment contributes to the pro-tumorigenic polarization of ovarian carcinoma TAMs. This conclusion is supported by the association of high ANGPTL4 expression with a shorter relapse-free survival in serous ovarian carcinoma.