结肠癌细胞分泌TERRA经HIF1α诱导衰老相关分泌表型促肺转移前微环境形成的机制研究

结肠癌肺转移的治疗和预后与肝转移差别较大。可能因为肺转移的微环境调控机制不同于肝转移。转移前微环境是原发肿瘤细胞通过信使分子在靶器官诱导的支持性微环境，炎症因子分泌是其普遍特征。衰老相关分泌表型（SASP）与多种肿瘤的转移前微环境相关。我们前期发现：结肠癌细胞与肺成纤维细胞共培养后能激活后者分泌SASP因子，但机制不明。预实验发现肠癌细胞外分泌一种含端粒序列RNA--TERRA，进入肺成纤维细胞并与HIF1α作用激活肺间质SASP因子上调，并证实该途径产生的SASP是肺转移灶形成的重要条件。但TERRA与HIF1α作用机制尚不明确。本项目拟在原代细胞、裸鼠模型和临床病例水平，研究TERRA与HIF1α的作用机制及其对SASP因子组蛋白的修饰机制。阐明癌细胞分泌TERRA诱导肺转移前微环境的分子机制。本研究可能为结肠癌肺转移提供新的理论基础和潜在治疗靶点。

The treatment and prognosis of lung metastasis of colon cancer are different from that of liver metastasis. The possible reason is that the microenvironmental regulation mechanism of lung metastasis is different from that of liver metastasis.Pre-metastatic niche is a secondary-organ microenvironment induced by primary cancer cells by secreting certain messenger molecule. Inflammatory factors are very common phenotype of such niche. Senescence associated secretory phenotype(SASP) is a group of inflammatory factors closely related to tumor microenvironment.Our previous study found that,when co-cultured with Colorectal cancer cells(CRCs), lung fibroblast cells (LF)displays increased SASP secretion, with unknown mechanism. Further study indicated that CRCs secret a type of long non-coding RNA, telomere-regulating RNA(TERRA),into circulation and selectively enters LH cells. These CRC-derived TERRA in LF then interact with HIF1α, transcriptionally inducing SASP factors expression through histone acetylation. Our preliminary data has shown in clinical case and animal model that TERRA-HIF1α pathway induced SASP secretion is a critical condition for circulating CRC to colonize in lung stroma.However, the mechanism underlying TERRA interacting with HIF1α is still unclear.Here in the current proposal, we plan to using primary cells, PDX animal model and patient sample to explore the detailed molecular mechanism of how TERRA and HIF1α interact trigger the secretion of SASP, which in turn form a hospital environment for disseminated cancer cells. Our study set goal to provide new mechanism perspective and new therapeutic target for CRC lung metastasis.