Gao Peng, Ren Guanghui, Liang Jiangjiu, Liu Ju
Department of Gerontology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.
Institute of Microvascular Medicine, Medical Research Center, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, China.
Front Oncol. 2022 May 5;12:823377. doi: 10.3389/fonc.2022.823377. eCollection 2022.
The role of signal transducer and activator of transcription 6 (STAT6) in tumor growth has been widely recognized. However, its effects on the regulation of angiogenesis remain unclear. In this study, we found that STAT6 promoted angiogenesis, possibly by increasing the expression of neuropilin-1 (NRP1) in endothelial cells (ECs). Both STAT6 inhibitor (AS1517499) and STAT6 siRNA reduced EC proliferation, migration, and tube-formation, accompanied by downregulation of NRP1, an angiogenesis regulator. Furthermore, IL-13 induced activation of STAT6 and then increased NRP1 expression in ECs. IL-13-induced EC migration and tube formation were inhibited by NRP1 siRNA. Luciferase assay and chromatin immunoprecipitation assay demonstrated that STAT6 could directly bind to human NRP1 promoter and increase the promoter activity. In tumor xenograft models, inhibition of STAT6 reduced xenograft growth, tumor angiogenesis, and NRP1 expression . Overall, these results clarified the novel mechanism by which STAT6 regulates angiogenesis, and suggested that STAT6 may be a potential target for anti-angiogenesis therapy.
信号转导及转录激活因子6（STAT6）在肿瘤生长中的作用已得到广泛认可。然而，其对血管生成调节的影响仍不清楚。在本研究中，我们发现STAT6可能通过增加内皮细胞（ECs）中神经纤毛蛋白-1（NRP1）的表达来促进血管生成。STAT6抑制剂（AS1517499）和STAT6 siRNA均降低了EC的增殖、迁移和管腔形成，同时伴随着血管生成调节因子NRP1的下调。此外，IL-13诱导STAT6激活，进而增加ECs中NRP1的表达。NRP1 siRNA抑制了IL-13诱导的EC迁移和管腔形成。荧光素酶报告基因检测和染色质免疫沉淀检测表明，STAT6可直接结合人NRP1启动子并增加启动子活性。在肿瘤异种移植模型中，抑制STAT6可减少异种移植瘤的生长、肿瘤血管生成及NRP1表达。总体而言，这些结果阐明了STAT6调节血管生成的新机制，并提示STAT6可能是抗血管生成治疗的潜在靶点。
