CXCL16/CXCR6轴通过诱导MSC-肺癌杂交瘤细胞EMT促进肺癌转移的作用及分子机制研究

项目名称： CXCL16/CXCR6轴通过诱导MSC-肺癌杂交瘤细胞EMT促进肺癌转移的作用及分子机制研究

项目编号： No.81472697

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 刘国祥

作者单位： 中国人民解放军第三军医大学

项目金额： 64万元

中文摘要： 在面上项目30871123支助下，我们发现骨髓来源间充质干细胞（MSC）能向肺癌病灶归巢，且与肺癌EMT相关。在面上项目81071728支助下，我们检测到MSC可与肺癌细胞在体内、外自发融合，产生的杂交瘤细胞具有EMT特性，然而其调控机制不明。本课题组前期研究发现，杂交瘤细胞同时高表达CXCR6和CXCL16，且与EMT密切相关，而抑制JAK2/STAT3通路可明显抑制杂交瘤细胞EMT发生。据此推测CRCL16/CXCR6轴可能通过JAK2/STAT3通路调控杂交瘤细胞发生EMT的假说。本课题拟构建肺癌动物模型及体外培养杂交瘤细胞，通过增强和干扰CXCL16/CXCR6轴观察对EMT的影响，并检测JAK2/STAT3通路、下游PI3K以及twist、snail等EMT关键调控因子的基因及蛋白的变化。最后通过临床标本验证。为阐明肺癌早期转移机制及制定新的靶向治疗措施抑制肺癌转移提供实验依据。

中文关键词： C05_气管；支气管；肺肿瘤；间充质干细胞；CXCL16/CXCR6轴；上皮-间质转化；转移

英文摘要： Supported by grants from the National Natural Science Foundation of China (30871123), we observed that a variety of mesenchymal stem cells (MSCs) from the bone marrow are recruited to tumor sites, and play a role in facilitating epithelial mesenchymal transition(EMT). Supported by grants from the National Natural Science Foundation of China (81071728), we found that MSCs could facilitate the ability of tumor cells to acquire mesenchymal properties during a physical fusion event with lung cancer cells. However, the undrelying mechanism remains unclear. Our previous research showed, hybrids formed by fusion between human lung cancer cells and bone marrow-derived MSCs overproduce both CXCR6 and CXCL16 and correlated with EMT. JAK2 inhibitor can effectively inhibit EMT. Based on our previous reserch, we hypothesized that MSCs might promote EMT through fusion with lung cancer cells by CXCL16/CXCR6 axis mediated JAK2/STAT3 pathway. In order to verify the hypothesis, we plan to use a murine model of lung cancer and culture MSC-lung cancer hybrids to observe whether CXCL16/CXCR6 axis are used by hybrids to acquire mesenchymal properties and test JAK2/STAT3 pathway、PI3K and expression of EMT related transcription factors to elucidate the underlying mechanism. Finally verify through clinical research. These findings may explain how lug cancer cells acquire a motile phenotype so early and represent viable entities for the design of targeting therapies to prevent the establishment of distant metastasis of lung cancers cells.

英文关键词： lung cancer;mesenchymal stem cells;CXCL16/CXCR6 axis;epithelial-mesenchymal transition;metastasis