文章：

MICA阳性肿瘤细胞通过PPAR/EHHADH介导的脂肪酸代谢调控肝细胞癌中巨噬细胞表型与功能

MICA+ Tumor Cells Modulate Macrophage Phenotype and Function via PPAR/EHHADH-Mediated Fatty Acid Metabolism in Hepatocellular Carcinoma (HCC)

原文发布日期：16 July 2025

DOI: 10.3390/cancers17142365

类型: Article

开放获取: 是

英文摘要：

Background:Tumor-associated macrophages (TAMs) play a crucial role in the tumor microenvironment (TME), and the metabolic activities of both tumor cells and TAMs have an impact on the TME. Moreover, the expression of MICA in tumor cells is closely associated with immune cells in hepatocellular carcinoma (HCC). However, it remains unclear whether MICA expression correlates with TAMs and influences the switch in macrophage phenotype by mediating metabolic alterations.Methods:Various biostatistical tools, qPCR, and IHC staining experiments were utilized to analyze data from The Cancer Genome Atlas (TCGA) and collected HCC tumor tissues. Single-cell RNA sequencing (scRNA-seq) analyses and a co-culture model of HCC cells with macrophages were performed to validate the findings from the biostatistical analyses.Results:Through the intersection of differentially expressed genes (DEGs), metabolism-related genes (MRGs), and co-expression genes (CEGs) with MICA in HCC, the EHHADH gene was identified. Gene set enrichment analyses were conducted to further confirm the role of EHHADH. EHHADH expression is decreased in HCC tumors and can serve as a prognostic biomarker for HCC. Expressions of MICA and EHHADH exhibited significant correlations with various phenotypic macrophages and exerted opposing effects on M1-like and M2-like macrophages infiltrating HCC. The underlying metabolic and molecular mechanisms revealed that MICA in tumor cells induced M2-like polarization through the PPAR/EHHADH pathway, which regulates the fatty acid oxidation (FAO) in macrophages.Conclusions:The metabolic gene EHHADH, which is associated with MICA, led to alterations in M2-like macrophages by promoting heightened fatty acid uptake and augmenting levels of FAO within macrophages.

摘要翻译： 

背景：肿瘤相关巨噬细胞（TAMs）在肿瘤微环境（TME）中扮演关键角色，肿瘤细胞与TAMs的代谢活动均对TME产生影响。此外，肿瘤细胞中MICA的表达与肝细胞癌（HCC）中的免疫细胞密切相关。然而，MICA表达是否与TAMs相关，并通过介导代谢改变影响巨噬细胞表型转换，目前尚不明确。 方法：本研究综合运用多种生物统计学工具、qPCR及免疫组化染色实验，对癌症基因组图谱（TCGA）数据库及收集的HCC肿瘤组织数据进行分析。通过单细胞RNA测序（scRNA-seq）分析及HCC细胞与巨噬细胞共培养模型，验证生物统计学分析结果。 结果：通过对HCC中差异表达基因（DEGs）、代谢相关基因（MRGs）及与MICA共表达基因（CEGs）进行交叉分析，鉴定出EHHADH基因。基因集富集分析进一步证实了EHHADH的功能。EHHADH在HCC肿瘤组织中表达下调，可作为HCC预后生物标志物。MICA与EHHADH的表达与多种表型巨噬细胞显著相关，并对浸润HCC的M1型与M2型巨噬细胞产生相反调控作用。机制研究表明，肿瘤细胞中MICA通过PPAR/EHHADH通路诱导巨噬细胞向M2型极化，该通路调控巨噬细胞中的脂肪酸氧化（FAO）过程。 结论：与MICA相关的代谢基因EHHADH通过促进巨噬细胞增强脂肪酸摄取并提高FAO水平，导致M2型巨噬细胞发生功能性改变。

原文链接：

MICA+ Tumor Cells Modulate Macrophage Phenotype and Function via PPAR/EHHADH-Mediated Fatty Acid Metabolism in Hepatocellular Carcinoma (HCC)