CX3CL1/CX3CR1信号通路调节胰腺癌糖代谢的分子机制研究

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.

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。

肿瘤细胞可以通过复杂的调节机制适应胰腺癌恶劣的乏氧低糖微环境，我们的研究旨在探讨CX3CL1/CX3CR1通路调节胰腺癌细胞糖摄取能力的机制。我们发现HIF1A是CX3CL1/CX3CR1影响胰腺癌细胞的糖摄取的重要分子，CX3CL1/CX3CL1可上调HIF1A的表达并通过其发挥作用。HIF1A进一步通过LIMS1增加GLUT1表达和膜易位，并促进肿瘤细胞适应葡萄糖剥夺应激。LIMS1又通过激活AKT/mTOR信号刺激HIF-1A的翻译活性，形成正反馈环路。我们后续针对上述糖代谢异常设计了纳米载体开展临床前实验，该药物表现出了显著的抑瘤作用，有良好的应用前景。