Center for Precision Medicine, School of Medicine and School of Biomedical Sciences, Huaqiao University, Xiamen 361021, China.
Departments of Radiation Oncology, First Hospital of Quanzhou Affiliated to Fujian Medical University, Quanzhou 362000, China.
Curr Oncol. 2022 Oct 14;29(10):7680-7694. doi: 10.3390/curroncol29100607.
Esophageal squamous cell carcinoma (ESCC) is a type of progressive and distant metastatic tumor. Targeting anti-angiogenic genes could effectively hinder ESCC development and metastasis, whereas ESCC locating on the upper or the lower esophagus showed different response to the same clinical treatment, suggesting ESCC location should be taken into account when exploring new therapeutic targets. In the current study, to find novel anti-angiogenic therapeutic targets, we identified endothelial cell subsets in upper and lower human ESCC using single-cell RNA sequencing (scRNA-seq), screened differentially expressed genes (DEGs), and performed gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. The results showed that common DEGs shared in the upper and the lower endothelial cells mainly are involved in vessel development, angiogenesis, and cell motility of endothelial cells by regulating PI3K-AKT, Rap1, Ras, TGF-beta, and Apelin signaling pathways. The critical regulatory genes were identified as , , , , , , , , , , , , , and . Cell metabolism-relevant genes, e.g., , , , and might be the prospective therapeutic targets. Furthermore, we found that DEGs only in the upper endothelial cells, such as , , , , , , , and , mainly regulated cell adhesion, structure morphogenesis, and motility through Phospholipase D, Apelin, and VEGF signaling pathways. Moreover, DEGs only in the lower endothelial cells, for instance , , , and , mainly regulated cell apoptosis and survival by targeting calcium ion transport through Rap1, Ras, cAMP, Phospholipase D, and Phosphatidylinositol signaling pathways. In addition, the upper endothelial cells showed significant functional diversity such as cytokine-responsive, migratory, and proliferative capacity, presenting a better angiogenic capacity and making it more sensitive to anti-angiogenic therapy compared with the lower endothelial cells. Our study has identified the potential targeted genes for anti-angiogenic therapy for both upper and lower ESCC, and further indicated that anti-angiogenic therapy might be more effective for upper ESCC, which still need to be further examined in the future.
食管鳞状细胞癌（ESCC）是一种进行性和远处转移性肿瘤。针对抗血管生成基因可以有效地抑制 ESCC 的发展和转移，然而 ESCC 位于食管的上部或下部对相同的临床治疗反应不同，这表明在探索新的治疗靶点时应考虑 ESCC 的位置。在本研究中，为了寻找新的抗血管生成治疗靶点，我们使用单细胞 RNA 测序（scRNA-seq）鉴定了人 ESCC 上、下部的内皮细胞亚群，筛选差异表达基因（DEGs），并进行基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析。结果表明，上、下部内皮细胞中共同的 DEGs 主要涉及血管发育、血管生成和内皮细胞的细胞运动，通过调节 PI3K-AKT、Rap1、Ras、TGF-β和 Apelin 信号通路。关键调控基因被鉴定为、、、、、、、、、、、、、和。细胞代谢相关基因，如、、、和，可能是有前途的治疗靶点。此外，我们发现仅在上皮细胞中表达的 DEGs，如、、、、、、、和，主要通过磷脂酶 D、Apelin 和 VEGF 信号通路调节细胞黏附、结构形态发生和运动。此外，仅在下皮细胞中表达的 DEGs，如、、和，主要通过靶向 Rap1、Ras、cAMP、磷脂酶 D 和磷脂酰肌醇信号通路调节细胞凋亡和存活。此外，上皮细胞表现出明显的功能多样性，如细胞因子反应性、迁移性和增殖能力，表现出更好的血管生成能力，并且与下部内皮细胞相比，对抗血管生成治疗更敏感。我们的研究鉴定了上、下部 ESCC 抗血管生成治疗的潜在靶向基因，并进一步表明抗血管生成治疗对上 ESCC 可能更有效，这仍需在未来进一步研究。
