半胱氨酰白三烯激活ATF-2上调VCAM-1表达促进肺预转移小生境形成的机制研究

肺预转移小生境形成是肿瘤发生肺转移的重要步骤。炎症反应是预转移小生境的特征之一。半胱氨酰白三烯在预转移小生境中表达升高，促进肿瘤转移。但是，半胱氨酰白三烯对预转移小生境形成的影响尚不清楚。我们前期发现：预转移小生境中VCAM-1表达升高。研究表明，半胱氨酰白三烯上调血管内皮细胞表面的VCAM-1。VCAM-1介导白细胞与内皮细胞黏附，促进炎症反应。我们推测：半胱氨酰白三烯通过激活ATF-2上调VCAM-1表达，促进炎症反应，诱导预转移小生境形成。本项目以肺转移动物模型和HUVEC为研究对象，拟采用血管通透性实验、癌细胞渗出实验、免疫共沉淀、基因敲低和过表达等技术研究半胱氨酰白三烯对预转移小生境的影响及机制，并探讨c-Jun、c-Fos、NF-κB是否与ATF-2共同促进VCAM-1表达。本项目将为以半胱氨酰白三烯为靶点防治肿瘤转移提供依据，并揭示ATF-2上调VCAM-1表达的机制。

The formation of lung pre-metastatic niche is a critical step of lung metastasis. Inflammation is one of the characteristics of pre-metastatic niche. The level of cysteinyl leukotrienes (cys-LTs) is elevated in the pre-metastatic niche and it promotes tumor metastasis. But the effect of cys-LTs on the formation of pre-metastatic niche remains unclear. We previously found that the expression of vascular cell adhesion molecule-1 (VCAM-1) was increased in the pre-metastatic niche. It was reported that cys-LTs promoted the expression of VCAM-1 on the surface of vascular endothelial cells. VCAM-1 mediates the adhesion between leukocytes and endothelial cells, and promotes inflammation. We speculate that cys-LTs may activate ATF-2 to induce VCAM-1 expression then promote the formation of lung pre-metastatic niche. In vivo, the 4T1 breast cancer cells and Balb/c mice were used to establish animal models. In vitro, HUVEC is used as the research materials. The technology of vascular permeability assay, cancer cell exudation assay, immunoprecipitation, gene knockdown and overexpression were employed to study the effect and mechanism of cys-LTs on the formation of pre-metastatic niche. We will also explore whether ATF-2 promote VCAM-1 expression cooperate with c-Jun, c-Fos and NF-κB. Our project will provide new ideas for the prevention and treatment of tumor metastasis with cys-LTs as the target, and further explore the mechanism of ATF-2 promotes VCAM-1 expression.