Song Huangqin, Wang Xiaoxiao, Zhang Chao, He Jiefeng
Third Hospital of Shanxi Medical University, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Taiyuan, China.
Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, China.
Front Oncol. 2023 Jun 20;13:1170775. doi: 10.3389/fonc.2023.1170775. eCollection 2023.
M2 macrophages play a crucial role in promoting tumor angiogenesis and proliferation, as well as contributing to chemotherapy resistance and metastasis. However, their specific role in the tumor progression of hepatocellular carcinoma (HCC) and their impact on the clinical prognosis remain to be further elucidated.
M2 macrophage-related genes were screened using CIBERSORT and weighted gene co-expression network analysis (WGCNA), while subtype identification was performed using unsupervised clustering. Prognostic models were constructed using univariate analysis/least absolute shrinkage selector operator (LASSO) Cox regression. In addition, Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG), gene set enrichment analysis (GSEA), gene set variation analysis (GSVA), and mutation analysis were used for further analysis. The relationship between the risk score and tumor mutation burden (TMB), microsatellite instability (MSI), the efficacy of transcatheter arterial chemoembolization (TACE), immunotype, and the molecular subtypes were also investigated. Moreover, the potential role of the risk score was explored using the ESTIMATE and TIDE (tumor immune dysfunction and exclusion) algorithms and stemness indices, such as the mRNA expression-based stemness index (mRNAsi) and the DNA methylation-based index (mDNAsi). In addition, the R package "pRRophetic" was used to examine the correlation between the risk score and the chemotherapeutic response. Finally, the role of in HepG2 cells was investigated using various techniques, including Western blotting, RT-PCR and Transwell and wound healing assays.
This study identified 158 M2 macrophage-related genes enriched in small molecule catabolic processes and fatty acid metabolic processes in HCC. Two M2 macrophage-related subtypes were found and a four-gene prognostic model was developed, revealing a positive correlation between the risk score and advanced stage/grade. The high-risk group exhibited higher proliferation and invasion capacity, MSI, and degree of stemness. The risk score was identified as a promising prognostic marker for TACE response, and the high-risk subgroup showed higher sensitivity to chemotherapeutic drugs (e.g., sorafenib, doxorubicin, cisplatin, and mitomycin) and immune checkpoint inhibitor (ICI) treatments. The expression levels of four genes related to the macrophage-related risk score were investigated, with and showing low expression and and exhibiting high expression in HCC. experiments showed that may enhance the migration ability of HepG2 cells by activating the Wnt signaling pathway.
We identified 158 HCC-related M2 macrophage genes and constructed an M2 macrophage-related prognostic model. This study advances the understanding of the role of M2 macrophages in HCC and proposes new prognostic markers and therapeutic targets.
M2巨噬细胞在促进肿瘤血管生成和增殖以及导致化疗耐药和转移方面发挥着关键作用。然而，它们在肝细胞癌（HCC）肿瘤进展中的具体作用及其对临床预后的影响仍有待进一步阐明。
使用CIBERSORT和加权基因共表达网络分析（WGCNA）筛选M2巨噬细胞相关基因，同时使用无监督聚类进行亚型鉴定。使用单变量分析/最小绝对收缩选择算子（LASSO）Cox回归构建预后模型。此外，利用基因本体论（GO）/京都基因与基因组百科全书（KEGG）、基因集富集分析（GSEA）、基因集变异分析（GSVA）和突变分析进行进一步分析。还研究了风险评分与肿瘤突变负荷（TMB）、微卫星不稳定性（MSI）、经动脉化疗栓塞（TACE）疗效、免疫类型和分子亚型之间的关系。此外，使用ESTIMATE和TIDE（肿瘤免疫功能障碍和排除）算法以及干性指数，如基于mRNA表达的干性指数（mRNAsi）和基于DNA甲基化的指数（mDNAsi），探索风险评分的潜在作用。此外，使用R包“pRRophetic”来检查风险评分与化疗反应之间的相关性。最后，使用包括蛋白质免疫印迹、逆转录-聚合酶链反应（RT-PCR）以及Transwell和伤口愈合试验等各种技术研究了[此处原文缺失具体基因名称]在HepG2细胞中的作用。
本研究鉴定出158个在HCC的小分子分解代谢过程和脂肪酸代谢过程中富集的M2巨噬细胞相关基因。发现了两种M2巨噬细胞相关亚型，并建立了一个四基因预后模型，揭示了风险评分与晚期/高级别之间的正相关。高危组表现出更高的增殖和侵袭能力、MSI以及干性程度。风险评分被确定为TACE反应的一个有前景的预后标志物，高危亚组对化疗药物（如索拉非尼、阿霉素、顺铂和丝裂霉素）和免疫检查点抑制剂（ICI）治疗表现出更高的敏感性。研究了与巨噬细胞相关风险评分相关的四个基因的表达水平，[此处原文缺失具体基因名称]在HCC中表现出低表达，而[此处原文缺失具体基因名称]表现出高表达。[此处原文缺失具体实验名称]实验表明，[此处原文缺失具体基因名称]可能通过激活Wnt信号通路增强HepG2细胞的迁移能力。
我们鉴定出158个与HCC相关的M2巨噬细胞基因，并构建了一个与M2巨噬细胞相关的预后模型。本研究推进了对M2巨噬细胞在HCC中作用的理解，并提出了新的预后标志物和治疗靶点。
