oHA-LYVE1-S1P3通路调节淋巴内皮细胞孔隙改变在肿瘤淋巴转移中的作用及机制研究

项目名称： oHA-LYVE1-S1P3通路调节淋巴内皮细胞孔隙改变在肿瘤淋巴转移中的作用及机制研究

项目编号： No.81502490

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 杜艳

作者单位： 上海交通大学

项目金额： 17万元

中文摘要： 淋巴管腔通透性增加是肿瘤淋巴转移过程中的初始步骤，具体调控机制不明。据报道，肿瘤微环境中细胞外基质主要成分透明质酸HA及其降解片段oHA，通过其受体CD44在调节血管通透性中发挥重要作用，但是其是否可调节淋巴管壁通透性，尚需验证。综合本课题前期及他人研究发现，肿瘤组织液及血清中oHA与淋巴转移正相关；我们预实验结果发现，oHA能够促进黑色素瘤细胞的淋巴转移，并且转移组淋巴管腔间隙较未转移组明显扩大。这些结果对阐明oHA在肿瘤淋巴转移中的作用、方式及机制，有重要的提示性。LYVE1是淋巴管壁上HA的唯一受体，与CD44同源，差别为分布不同。S1P3是内皮细胞1-磷酸鞘氨醇受体亚型，与CD44共作用调控血管渗透性。但S1P3是否与LYVE-1共作用调控淋巴管通透性，尚无相关研究。根据这一特点，本课题拟通过体内外实验研究，探索oHA是否通过LYVE1-S1P3途径调控肿瘤淋巴转移的作用及机制。

中文关键词： 淋巴转移；细胞外基质；透明质酸寡分子

英文摘要： The increasing of lymphatic vessel permeability is the initial step on tumor lymphatic metastasis, but specific regulatory mechanism is unknown. It has been reported that hyaluronic acid(HA) and its degradation fragments(oHA), the main component of extracellular matrix in tumor microenvironment, could play an important role in regulating vascular permeability through its receptor CD44,but whether oHA could adjust the permeability of lymphatic vessel need to be proved. Based on our previously and others study, it was found that the oHA in tumor tissue fluid and serum were positive related with tumor lymph metastasis. Our preliminary experimental results found that oHA stimulation significantly increased melanoma lymphatic metastasis. The lymphatic vessels spaces in metastases group were clearly dilated compared with metastasis negative group. These results could help for clarifing the role, the mode and the mechanism on tumor lymphatic metastasis by oHA. LYVE1 is the only HA receptor on lymphatic vessels. LYVE1 is homology with CD44, the difference is distribution different. S1P3 is the subtype of sphingosine-1-phosphate receptors. It could bind CD44 to regulate the permeability of vasular. There is no related research on regulating the permeability of lymph vessel by binding SP3 to LYVE1. According to this characteristic, our study proposed to explore the function and the mechanism of oHA on regulating tumor lymphatic metastasis through LYVE1-S1P3 pathways by vivo and vitro experiments.

英文关键词： lymph metastasis;ECM;oHA