Notch信号转录抑制DMT1调节细胞内铁代谢参与血管壁细胞表型转换及肿瘤血管正常化的机制研究

肿瘤血管结构功能的紊乱促进肿瘤恶性进展，血管壁细胞表型可塑性引起的壁细胞功能失常是血管异常的关键因素，然而，调控肿瘤壁细胞表型转换的分子机制尚不明确。申请人前期研究表明，肿瘤微环境壁细胞中Notch信号处于抑制状态，活化Notch信号可促进壁细胞收缩蛋白的表达，抑制其炎性分泌表型，促进肿瘤血管正常化，抑制肿瘤进展，并伴随铁代谢相关通路的抑制、关键转运分子DMT-1表达的下降，和细胞内铁含量的降低。预实验结果表明，铁过载可消除Notch信号介导的壁细胞表型调控效应。因此，Notch信号可能通过降低细胞内铁含量调控壁细胞表型转化过程，促进血管正常化。本课题拟进一步明确Notch信号通过DMT-1调控细胞内铁稳态的作用和机制，阐明细胞内铁在壁细胞表型转换中的细胞生物学功能，揭示“Notch信号-铁代谢”调控的壁细胞表型转化在肿瘤血管正常化及肿瘤进展中的意义，为肿瘤血管正常化治疗策略提供新的靶点。

The disorder of tumor vascular structure and function promotes the malignant progression of tumor. Vascular mural cell dysfunction caused by vascular mural cell phenotypic plasticity is the key factor of vascular abnormalities. However, the molecular mechanism of regulating tumor mural cell phenotypic transformation remains unclear. Our previous studies have indicated that Notch signaling in tumor microenvironment mural cells is inhibited. Activation of Notch signaling can promote the expression of contractile proteins in mural cells, inhibit their inflammatory secretion phenotype, promote the normalization of tumor vessels, inhibit tumor progression, and accompany with the inhibition of iron metabolism-related pathways and the decrease of the expression of DMT-1, a key transport molecule of iron metabolism. The results of the pre-experiment showed that iron overload could eliminate the effect of Notch signaling on the regulation of mural cell phenotype. Therefore, Notch signaling may regulate the phenotypic transformation of mural cells and promote vessel normalization by reducing intracellular iron content. This project aims to further clarify the role and mechanism of Notch signaling in regulating intracellular iron homeostasis through DMT-1, clarify the cellular biological function of intracellular iron in mural cell phenotypic transformation, and reveal the significance of "Notch signaling-iron metabolism"-regulated mural cell phenotypic transformation in tumor vessel normalization and tumor progression, so as to provide a new therapeutic target for the treatment strategy of tumor vessel normalization.