肝癌微环境中CCL15/16-CCR1轴的生物学意义

受趋化因子系统精密调控的炎症/免疫微环境是影响肝癌转移复发的重要因素。我们前期对肝癌微环境中趋化因子进行全面筛查后发现：CCL15、CCL16特异性高表达，可刺激肝癌细胞，招募CCR1+CD14+炎症细胞，促进肝癌进展。本项目将首先明确CCL15/16在微环境的细胞定位及临床意义，进而通过细胞共培养、体内外趋化模拟和干预模型研究，拟阐明："CCL15/CCL16-CCR1轴"所介导的促癌炎症/免疫微环境及后续的放大效应（即：促癌微环境进一步上调CCL15/16表达）是促进肝癌侵袭转移的重要因素，两者之间存在以"微环境细胞因子网络"为链接的正反馈；同时，"CCL15/CCL16-CCR1轴"可直接影响肝癌细胞本身的侵袭特性。调控CCL15/CCL16表达，或利用CCL15/CCL16的趋化特性，打破这一恶性循环有助于降低/逆转肝癌侵袭潜能，同时恢复肿瘤微环境的抗癌反应，减少肝癌复发。

The local immune and inflammatory microenvironment, which is strictly controled by chemokine network,play a crucial role in the metastasis and recurrence of hepatocellular carcinoma (HCC). In our priliminary study, after scrutinizing the chemokine network in HCC, we identified that CCL15 and CCL16 expressed in a perticularly high level in HCC tissue, which could not only stimulate HCC cell motility, but also recrute CCR1+CD14+ pro-tumor inflammatory cells, resulting in HCC progression. Based on the above information, in this study, we will first elucidate the cell types in HCC that specifically express CCL15/16 and the cinical significance of CCL15/16. Then, using coculture analysis,specific chemotractant models and mice experiments for intervention, we will emphsis on the biological roles and the underly mechanisms of the "CCL15/16-CCR1 axis" in modulating the local immune and inflammatory microenvironment to a tumor promoting direction, which in turn upregulate the expression levels of CCL15/16 in tumor microenvironment. In addtion, our study will also investigate the effect and the associated molecullar mechnisms of "CCL15/16-CCR1 axis" on HCC cell invasion and metastasis. Modulating "CCL15/16-CCR1 axis" will repress the invasive potential of HCC cells, and re-programme the local immnune resoponse to a anti-tumor direction, leading to reduced HCC recurrence and improve survival.