Disease Biomarkers and Molecular Mechanisms Group, Institut d'Investigació Sanitària Pere Virgilii, Joan XXIII University Hospital, Universitat Rovira i Virgili, C/ Dr. Mallafré Guasch, 4. 43007, Tarragona, Spain.
Urology Unit, Joan XXIII University Hospital, Tarragona, Spain.
BMC Med. 2022 Aug 18;20(1):255. doi: 10.1186/s12916-022-02457-3.
Periprostatic adipose tissue (PPAT) plays a role in prostate cancer (PCa) progression. PPAT lipidomic composition study may allow us to understand the tumor metabolic microenvironment and provide new stratification factors.
We used ultra-high-performance liquid chromatography-mass spectrometry-based non-targeted lipidomics to profile lipids in the PPAT of 40 patients with PCa (n = 20 with low-risk and n = 20 high-risk). Partial least squares-discriminant analysis (PLS-DA) and variable importance in projection (VIP) analysis were used to identify the most relevant features of PPAT between low- and high-risk PCa, and metabolite set enrichment analysis was used to detect disrupted metabolic pathways. Metabolic crosstalk between PPAT and PCa cell lines (PC-3 and LNCaP) was studied using ex vivo experiments. Lipid uptake and lipid accumulation were measured. Lipid metabolic-related genes (SREBP1, FASN, ACACA, LIPE, PPARG, CD36, PNPLA2, FABP4, CPT1A, FATP5, ADIPOQ), inflammatory markers (IL-6, IL-1B, TNFα), and tumor-related markers (ESRRA, MMP-9, TWIST1) were measured by RT-qPCR.
Significant differences in the content of 67 lipid species were identified in PPAT samples between high- and low-risk PCa. PLS-DA and VIP analyses revealed a discriminating lipidomic panel between low- and high-risk PCa, suggesting the occurrence of disordered lipid metabolism in patients related to PCa aggressiveness. Functional analysis revealed that alterations in fatty acid biosynthesis, linoleic acid metabolism, and β-oxidation of very long-chain fatty acids had the greatest impact in the PPAT lipidome. Gene analyses of PPAT samples demonstrated that the expression of genes associated with de novo fatty acid synthesis such as FASN and ACACA were significantly lower in PPAT from high-risk PCa than in low-risk counterparts. This was accompanied by the overexpression of inflammatory markers (IL-6, IL-1B, and TNFα). Co-culture of PPAT explants with PCa cell lines revealed a reduced gene expression of lipid metabolic-related genes (CD36, FASN, PPARG, and CPT1A), contrary to that observed in co-cultured PCa cell lines. This was followed by an increase in lipid uptake and lipid accumulation in PCa cells. Tumor-related genes were increased in co-cultured PCa cell lines.
Disturbances in PPAT lipid metabolism of patients with high-risk PCa are associated with tumor cell metabolic changes.
前列腺周围脂肪组织（PPAT）在前列腺癌（PCa）的进展中发挥作用。PPAT 的脂质组学组成研究可能使我们能够了解肿瘤代谢微环境，并提供新的分层因素。
我们使用基于超高效液相色谱-质谱的非靶向脂质组学技术对 40 例 PCa 患者（低危组 n=20，高危组 n=20）的 PPAT 中的脂质进行了分析。采用偏最小二乘判别分析（PLS-DA）和变量重要性投影（VIP）分析来鉴定低危和高危 PCa 之间 PPAT 中最相关的特征，并采用代谢物集富集分析来检测受干扰的代谢途径。通过体外实验研究 PPAT 与 PCa 细胞系（PC-3 和 LNCaP）之间的代谢串扰。测量了脂质摄取和脂质积累。通过 RT-qPCR 测量了脂质代谢相关基因（SREBP1、FASN、ACACA、LIPE、PPARG、CD36、PNPLA2、FABP4、CPT1A、FATP5、ADIPOQ）、炎症标志物（IL-6、IL-1B、TNFα）和肿瘤相关标志物（ESRRA、MMP-9、TWIST1）。
在高危和低危 PCa 患者的 PPAT 样本中，鉴定出 67 种脂质物种的含量存在显著差异。PLS-DA 和 VIP 分析显示，低危和高危 PCa 之间存在区分脂质组学的面板，提示与 PCa 侵袭性相关的患者发生紊乱的脂质代谢。功能分析表明，脂肪酸合成、亚油酸代谢和极长链脂肪酸的β氧化的改变对 PPAT 脂质组有最大影响。PPAT 样本的基因分析表明，与从头脂肪酸合成相关的基因（FASN 和 ACACA）在高危 PCa 的 PPAT 中的表达明显低于低危对应物。这伴随着炎症标志物（IL-6、IL-1B 和 TNFα）的过度表达。PPAT 外植体与 PCa 细胞系的共培养显示脂质代谢相关基因（CD36、FASN、PPARG 和 CPT1A）的基因表达降低，而与共培养的 PCa 细胞系观察到的情况相反。随后，PCa 细胞中的脂质摄取和脂质积累增加。与共培养的 PCa 细胞系相比，肿瘤相关基因增加。
高危 PCa 患者的 PPAT 脂质代谢紊乱与肿瘤细胞代谢变化有关。
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