全面分析人肝癌中 FOXM1 免疫浸润、m6A、糖酵解和 ceRNA 网络。
Comprehensive analysis of FOXM1 immune infiltrates, m6a, glycolysis and ceRNA network in human hepatocellular carcinoma.
机构信息
School of Pharmacy, Hunan University of Chinese Medicine, Changsha, China.
College of Biology, Hunan University, Changsha, China.
出版信息
Front Immunol. 2023 May 10;14:1138524. doi: 10.3389/fimmu.2023.1138524. eCollection 2023.
BACKGROUND
Forkhead box M1 (FOXM1) is a member of the Forkhead box (Fox) transcription factor family. It regulates cell mitosis, cell proliferation, and genome stability. However, the relationship between the expression of FOXM1 and the levels of m6a modification, immune infiltration, glycolysis, and ketone body metabolism in HCC has yet to be fully elucidated.
METHODS
Transcriptome and somatic mutation profiles of HCC were downloaded from the TCGA database. Somatic mutations were analyzed by maftools R package and visualized in oncoplots. GO, KEGG and GSEA function enrichment was performed on FOXM1 co-expression using R. We used Cox regression and machine learning algorithms (CIBERSORT, LASSO, random forest, and SVM-RFE) to study the prognostic value of FOXM1 and immune infiltrating characteristic immune cells in HCC. The relationship between FOXM1 and m6A modification, glycolysis, and ketone body metabolism were analyzed by RNA-seq and CHIP-seq. The competing endogenous RNA (ceRNA) network construction relies on the multiMiR R package, ENCORI, and miRNET platforms.
RESULTS
FOXM1 is highly expressed in HCC and is associated with a poorer prognosis. At the same time, the expression level of FOXM1 is significantly related to the T, N, and stage. Subsequently, based on the machine learning strategies, we found that the infiltration level of T follicular helper cells (Tfh) was a risk factor affecting the prognosis of HCC patients. The high infiltration of Tfh was significantly related to the poor overall survival rate of HCC. Besides, the CHIP-seq demonstrated that FOXM1 regulates m6a modification by binding to the promoter of IGF2BP3 and affects the glycolytic process by initiating the transcription of HK2 and PKM in HCC. A ceRNA network was successfully obtained, including FOXM1 - has-miR-125-5p - DANCR/MIR4435-2HG ceRNA network related to the prognosis of HCC.
CONCLUSION
Our study implicates that the aberrant infiltration of Tfh associated with FOXM1 is a crucial prognostic factor for HCC patients. FOXM1 regulates genes related to m6a modification and glycolysis at the transcriptional level. Furthermore, the specific ceRNA network can be used as a potential therapeutic target for HCC.
背景
叉头框 M1（FOXM1）是叉头框（Fox）转录因子家族的一员。它调节细胞有丝分裂、细胞增殖和基因组稳定性。然而，FOXM1 的表达与 HCC 中的 m6A 修饰、免疫浸润、糖酵解和酮体代谢水平之间的关系尚未完全阐明。
方法
从 TCGA 数据库中下载 HCC 的转录组和体细胞突变谱。使用 maftools R 包分析体细胞突变，并在 oncoplots 中可视化。使用 R 对 FOXM1 共表达进行 GO、KEGG 和 GSEA 功能富集。我们使用 Cox 回归和机器学习算法（CIBERSORT、LASSO、随机森林和 SVM-RFE）研究 FOXM1 与 HCC 中免疫浸润特征免疫细胞的预后价值。通过 RNA-seq 和 CHIP-seq 分析 FOXM1 与 m6A 修饰、糖酵解和酮体代谢的关系。竞争性内源 RNA（ceRNA）网络构建依赖于 multiMiR R 包、ENCORI 和 miRNET 平台。
结果
FOXM1 在 HCC 中高表达，与预后不良相关。同时，FOXM1 的表达水平与 T、N 和分期显著相关。随后，基于机器学习策略，我们发现滤泡辅助性 T 细胞（Tfh）的浸润水平是影响 HCC 患者预后的危险因素。Tfh 的高浸润与 HCC 患者总生存率的降低显著相关。此外，CHIP-seq 表明，FOXM1 通过与 IGF2BP3 启动子结合调节 m6A 修饰，并通过启动 HK2 和 PKM 在 HCC 中的转录来影响糖酵解过程。成功获得了包括 FOXM1-has-miR-125-5p-DANCR/MIR4435-2HG 在内的 ceRNA 网络，该网络与 HCC 的预后相关。
结论
我们的研究表明，与 FOXM1 相关的异常 Tfh 浸润是 HCC 患者的一个重要预后因素。FOXM1 调节与 m6A 修饰和糖酵解相关的基因在转录水平上。此外，特定的 ceRNA 网络可作为 HCC 的潜在治疗靶点。
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