Liver Transplantation Center, General Surgery, Huashan Hospital, Fudan University, Shanghai, China.
Institute of Organ Transplantation, Fudan University, Shanghai, China.
J Cancer Res Clin Oncol. 2024 Jun 19;150(6):311. doi: 10.1007/s00432-024-05849-5.
Metabolic reprogramming is an emerging hallmark that influences the tumour microenvironment (TME) by regulating the behavior of cancer cells and immune cells. The relationship between metabolism and immunity remains elusive. The purpose of this study was to explore the predictive value of immune- and metabolism-related genes in hepatocellular carcinoma (HCC) and their intricate interplay with TME.
We established the immune- and metabolism-related signature (IMRPS) based on the LIHC cohort from The Cancer Genome Atlas (TCGA) dataset. Kaplan-Meier analysis, receiver operating characteristic (ROC) curve analysis and Cox regression analysis confirmed the prognostic value of IMRPS. We investigated differences in immune cell infiltration, clinical features, and therapeutic response between risk groups. The quantitative real-time PCR (qPCR) was used to confirm the expression of signature genes. Immunohistochemical staining was performed to evaluate immune infiltration features in HCC tissue samples. We conducted cell experiments including gene knockout, cell counting kit-8 (CCK-8), and flow cytometry to explore the role of the IMRPS key gene UCK2 in HCC. RNA-seq was used to further investigate the potential underlying mechanism involved.
The IMRPS, composed of four genes, SMS, UCK2, PFKFB4 and MAPT, exhibited significant correlations with survival, immune cell infiltration, clinical features, immune checkpoints and therapeutic response. The IMRPS was shown to be an excellent predictor of HCC prognosis. It could stratify patients appropriately and characterize the TME accurately. The high-risk HCC group exhibited an immunosuppressive microenvironment with abundant M-like macrophage infiltration, which was confirmed by the immunohistochemistry results. The results of qPCR revealed that the expression of signature genes in 20 HCC tissues was significantly greater than that in adjacent normal tissues. After the key gene UCK2 was knocked out, the proliferation of the Huh7 cell line was significantly inhibited, and monocyte-derived macrophages polarized towards an M1-like phenotype in the coculture system. RNA-seq and GSEA suggested that the phenotypes were closely related to the negative regulation of growth and regulation of macrophage chemotaxis.
This study established a new IMRS for the accurate prediction of patient prognosis and the TME, which is also helpful for identifying new targets for the treatment of HCC.
代谢重编程是一个新兴的标志，通过调节癌细胞和免疫细胞的行为来影响肿瘤微环境（TME）。代谢与免疫之间的关系仍然难以捉摸。本研究旨在探讨肝癌（HCC）中免疫和代谢相关基因的预测价值及其与 TME 的复杂相互作用。
我们基于 TCGA 数据集的 LIHC 队列建立了免疫和代谢相关特征（IMRPS）。Kaplan-Meier 分析、接收者操作特征（ROC）曲线分析和 Cox 回归分析证实了 IMRPS 的预后价值。我们研究了风险组之间免疫细胞浸润、临床特征和治疗反应的差异。定量实时 PCR（qPCR）用于确认特征基因的表达。免疫组织化学染色用于评估 HCC 组织样本中的免疫浸润特征。我们进行了细胞实验，包括基因敲除、细胞计数试剂盒-8（CCK-8）和流式细胞术，以探讨 HCC 中 IMRPS 关键基因 UCK2 的作用。RNA-seq 用于进一步研究潜在的潜在机制。
由四个基因 SMS、UCK2、PFKFB4 和 MAPT 组成的 IMRPS 与生存、免疫细胞浸润、临床特征、免疫检查点和治疗反应显著相关。IMRPS 是 HCC 预后的极佳预测指标。它可以适当地对患者进行分层，并准确地描述 TME。高风险 HCC 组表现出免疫抑制的微环境，其中富含 M 样巨噬细胞浸润，免疫组织化学结果证实了这一点。qPCR 结果显示，20 例 HCC 组织中特征基因的表达明显高于相邻正常组织。关键基因 UCK2 敲除后，Huh7 细胞系的增殖明显受到抑制，在共培养系统中单核细胞衍生的巨噬细胞向 M1 样表型极化。RNA-seq 和 GSEA 表明表型与生长的负调节和巨噬细胞趋化性的调节密切相关。
本研究建立了一种新的免疫代谢风险评分（IMRS），用于准确预测患者预后和 TME，这也有助于确定 HCC 治疗的新靶点。
