CX3CL1/CX3CR1信号通路调节胰腺癌糖代谢的分子机制研究

项目名称： CX3CL1/CX3CR1信号通路调节胰腺癌糖代谢的分子机制研究

项目编号： No.31471340

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 生物科学

项目作者： 郝继辉

作者单位： 天津医科大学

项目金额： 85万元

中文摘要： CX3CL1/CX3CR1在胰腺癌中高表达并且与不良预后密切相关，但具体生物学功能尚未阐明。我们前期研究发现CX3CL1/CX3CR1促进胰腺癌细胞葡萄糖摄入和乳酸产生，提示该趋化因子可能参与调节胰腺癌的糖代谢。 本课题拟通过液相色谱-质谱联用的方法及PET-CT系统评价CX3CL1/CX3CR1信号对于胰腺癌糖代谢通路在体内外的影响，结合临床病理资料全面评价该信号对胰腺癌糖代谢的调节作用；从转录、翻译、细胞定位不同层次研究CX3CL1/CX3CR1对糖代谢关键基因HIF-1的调节机制，利用RNA测序筛选其它相关基因通路；进一步分析CX3CL1/CX3CR1通过调节糖代谢对线粒体结构、功能以及对胰腺癌细胞增殖、凋亡的影响。通过上述研究阐明CX3CL1/CX3CR1调节胰腺癌糖代谢的分子机制及意义，为研究趋化因子和肿瘤糖代谢的关系开拓新的思路。

中文关键词： 糖代谢；线粒体；CX3趋化因子；CX3趋化因子受体

英文摘要： CX3CL1/CX3CR1 signaling is overexpressed in pancreatic cancer and correlated with poor prognosis. Previously, we have shown that CX3CL1/CX3CR1 can induce the expression of HIF-1, which is the key transcriptional factor for reprogramming glucose metabolism. Additionally, recombinant CX3CL1 or overexpressed CX3CL1 could promote glucose uptake and lactate secretion in cultured pancreatic cancer cell lines. Therefore, we postulated that CX3CL1 was involved in the glucose metabolism of pancreatic cancer. In this study, we evaluated the role of CX3CL1/CX3CR1 in reprogramming glucose metabolism by LC-MS and PET-CT both in vitro and in vivo, as well as clinical pathological data. In addition, we aimed to clarify the mechanism of HIF-1 expression driven by CX3CL1/CX3CR1 at transcriptional level, translational level, as well as cellular location, and to screen other genetic pathways by RNA sequencing. Furthermore, we analyzed whether CX3CL1/CX3CR1, by changing glucose metabolism, regulated mitochondrial structure and function, or even the pancreatic cancer cells proliferation and apoptosis. In summary, the purpose of this study is to elucidate the molecular mechanism of glucose metabolism reprogrammed by CX3CL1/CX3CR1 signaling，thus providing new viewpoints for the understanding of the relationships between chemokines and glucose metabolism.

英文关键词： glucose metabolism;mitochondria;CX3CL1;CX3CR1