HIF-1调控外泌体中IGFBP2促进胰腺癌肝转移作用机制的研究

Exosomes are tiny vesicas secreted by living cells, which play major role in biological process by transferring bioactive molecules ,such as protein, to their receptors. Hypoxia microenvironment would promote tumor metastasis by regulating the protein expression in exosomes. In this study ,we focused on the effect of HIF-1, a transcriptional factor , on exosomes in hypoxia environment. Our preliminary data suggested that the injection of exosomes from HIF-1 overexpression Panc-02 cell lines through tail vail in orthotropic pancreatic cancer mouse model may promote the liver metastasis. By quantitative proteomic analysis and in silic study,we found the expression of insulin like growth factor binding protein 2 is elevated and NF-kB pathway was activated as well.Based on the data, we attempt to elucidate the mechanism of how HIF-1 regulates IGFBP2 expression, which in turn activates NF-kB pathway and facilitates the formation of "pre-metastatic niche" with stromal cells and finally accelerates tumor metastasis.To achieve the goal,we set up a orthotropic pancreatic cancer mouse model with bone marrow transplantation and a series molecular biological methods. We expect to search for new therapeutic target of pancreatic cancer liver metastasis from our study.

外泌体是活细胞分泌的小囊泡体, 能将其携带的蛋白质等生物活性分子传递给受体细胞而发挥生物学作用，乏氧微环境可能通过影响外泌体中蛋白的调控，促进肿瘤转移。本研究从乏氧微环境中的转录因子HIF-1对胰腺癌细胞来源外泌体的作用入手，提取HIF-1过表达的小鼠胰腺癌细胞株分泌的外泌体经尾静脉注射入胰腺癌原位小鼠模型发现肿瘤肝转移灶明显增多，通过定量蛋白组学和生物学信息筛选发现胰岛素样生长因子结合蛋白2表达存在明显差异，且NF-kB信号通路激活。基于以上前期工作，我们通过建立小鼠胰腺癌原位移植瘤转移模型及各种各种分子生物学手段，阐明HIF-1通过调控外泌体中IGFBP2蛋白的表达激活NF-kB信号通路，进而影响肿瘤间质细胞共同形成”预转移小生境“并引起胰腺癌肝转移发生的细胞及分子机制，为诊断治疗胰腺癌肝转移提供新的靶点。

外泌体是活细胞分泌的小囊泡体, 能将其携带的蛋白质等生物活性分子传递给受体细胞而发挥生物学作用，乏氧微环境可能通过影响外泌体中蛋白的调控，促进肿瘤转移。本研究从乏氧微环境中的转录因子HIF-1对胰腺癌细胞来源外泌体的作用入手，提取HIF-1过表达的小鼠胰腺癌细胞株分泌的外泌体经尾静脉注射入胰腺癌原位小鼠模型发现肿瘤肝转移灶明显增多，通过定量蛋白组学和生物学信息筛选发现胰岛素样生长因子结合蛋白2表达存在明显差异，且NF-kB信号通路激活。基于以上前期工作，我们通过建立小鼠胰腺癌原位移植瘤转移模型及各种各种分子生物学手段，阐明HIF-1通过调控外泌体中IGFBP2蛋白的表达激活NF-kB信号通路，进而影响肿瘤间质细胞共同形成”预转移小生境“并引起胰腺癌肝转移发生的细胞及分子机制，为诊断治疗胰腺癌肝转移提供新的靶点。