Endothelial cells (ECs) rely on glycolysis for energy production to maintain vascular homeostasis and the normalization of hyperglycolysis in tumor vessels has recently gained attention as a therapeutic target. We analyzed the TCGA database and found reduced Foxp1 expression in lung carcinoma. Immunostaining demonstrated reduced expression more restricted at tumor vascular ECs. Therefore, we investigated the function and mechanisms of Foxp1 in EC metabolism for tumor angiogenesis required for tumor growth. EC-Foxp1 deletion mice exhibited a significant increase of tumor and retinal developmental angiogenesis and Hif1α was identified as Foxp1 target gene, and Hk2 as Hif1α target gene. The Foxp1-Hif1α-Hk2 pathway in ECs is important in the regulation of glycolytic metabolism to govern tumor angiogenesis. Finally, we used genetic deletion of EC-Hif1α and RGD-peptide nanoparticles EC target delivery of Hif1α/Hk2-siRNAs to knockdown gene expression which reduced the tumor EC hyperglycolysis state and restricted angiogenesis for tumor growth. This study advances our understanding of EC metabolism for tumor angiogenesis, and meanwhile provides evidence for future therapeutic intervention of hyperglycolysis in tumor ECs for suppression of tumor growth.

中文翻译：

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ECs Foxp1靶向Hif1α-Hk2糖酵解信号限制血管生成的治疗效果


内皮细胞（EC）依靠糖酵解产生能量来维持血管稳态，肿瘤血管中糖酵解过度的正常化最近作为治疗靶点受到关注。我们分析了 TCGA 数据库，发现肺癌中 Foxp1 表达降低。免疫染色显示表达减少在肿瘤血管内皮细胞中受到更多限制。因此，我们研究了Foxp1在肿瘤生长所需的肿瘤血管生成的EC代谢中的功能和机制。 EC-Foxp1缺失小鼠表现出肿瘤和视网膜发育血管生成显着增加，Hif1α被确定为Foxp1靶基因，Hk2为Hif1α靶基因。 EC 中的 Foxp1-Hif1α-Hk2 通路对于调节糖酵解代谢以控制肿瘤血管生成非常重要。最后，我们使用 EC-Hif1α 的基因删除和 RGD-肽纳米粒子 EC 靶向递送 Hif1α/Hk2-siRNA 来敲低基因表达，从而降低肿瘤 EC 高糖酵解状态并限制肿瘤生长的血管生成。该研究增进了我们对肿瘤血管生成中EC代谢的认识，同时为未来通过高糖酵解干预肿瘤EC来抑制肿瘤生长提供了证据。