低氧下胰腺癌细胞外泌体来源的LncRNA-LUCAT1调控巨噬细胞M2型极化促进肿瘤转移的机制研究

低氧可调控外泌体分泌和巨噬细胞极化介导肿瘤转移，但机制不明。我们前期发现：低氧下胰腺癌细胞产生外泌体增多，调控巨噬细胞M2型极化，促进肿瘤细胞迁移侵袭；LncRNA-LUCAT1在低氧外泌体中高表达，可能结合于METTL3，与PI3Kγ活化有关。基于此，我们提出如下科学假说：低氧促进肿瘤细胞分泌外泌体，装载着LUCAT1传递到巨噬细胞与METTL3结合抑制其泛素化，激活PI3Kγ等通路，诱导巨噬细胞发生M2型极化，继而促进肿瘤转移。本项目将探讨：1.低氧促进外泌体产生调控巨噬细胞M2型极化的作用；2.低氧外泌体中LUCAT1调控巨噬细胞M2型极化促进肿瘤转移的机制；3.低氧下LUCAT1高表达机制；4.胰腺癌标本中Exo-LUCAT1的表达及临床意义。以上研究将阐明低氧下胰腺癌细胞外泌体来源的LUCAT1调控巨噬细胞M2型极化的作用机制，为胰腺癌转移防治和预后评估提供新的思路和靶点。

Hypoxia can regulate the secretion of exosomes and polarization of macrophages to promote tumor metastasis, but the mechanisms remain elusive. Previously, we found that the increased secretion of exosomes derived from pancreatic cancer cells under hypoxia regulated macrophages with M2 polarization, promoting the ability of invasion and metastasis of cancer cells. LncRNA-LUCAT1 highly expressing in the exosomes derived from PC cells under hypoxia, may bind to METTL3, which is associated with the activation of PI3Kγ. Based on this, we propose the following hypothesis: Hypoxia promotes secretion of exosomes in PC cells, which carry LUCAT1 to macrophages. And Exo-LUCAT1 activates PI3Kγ signaling pathway by inhibition of METTL3 ubiquitination, inducing M2 polarization of macrophages, thereby promoting metastasis of pancreatic cancer. This study aims to: 1. illustrate the role of hypoxia promoting exosomes secretion regulating M2 polarization of macrophages; 2. clarify the mechanism of LUCAT1 derived from hypoxic exosomes regulating the M2 polarization of macrophages to promote tumor metastasis; 3. explore the mechanism of hypoxia regulating the expression of exosomal LUCAT1; 4. analyze the expression and the clinical significance of LncRNA-LUCAT1 in pancreatic cancer. Thus, our study will clarify the role and mechanism of Exo-LncRNA-LUCAT1 from PC cells under hypoxia regulating macrophages with M2 polarization, and these findings should thereby ultimately contribute to the development of novel idea and target for the metastasis prevention and prognosis evaluation of pancreatic cancer.