胰腺癌细胞通过Hedgehog-外泌体MALAT-1途径促进周围神经侵犯的机制研究

Perineural invasion (PNI) is one of the leading causes of early metastasis and recurrence of pancreatic cancer. The “reciprocal signaling interaction” theory between tumor cells and nerves is the molecular basis of PNI. However, as the starting step in the signal interaction, it is unknown yet how the tumor cells transmit the signal to the nerve cells. In the previous study, we found that the Hedgehog(Hh) signaling pathway had a positive effect on MALAT-1 of exosome in pancreatic cancer cells. And then, the regulation relationship between MALAT-1, MiRNAs and two important PNI-related chemokines, CX3CL1 and GDNF was established by the combination of gene chips, bioinformatics analysis and in vitro experiment. Therefore, we speculated that the Hh signaling pathway in the pancreatic cancer cells regulated PNI process by up-regulating the transcription of MALAT-1, which started the reciprocal signaling interactions between pancreatic cancer cells and nerves by transporting and mediating by exosome. In this study, we will study the regulation mechanism of "Hh-exosome MALAT-1" pathway to nerve cells in pancreatic cancer, and further study the mechanism of interaction between pancreatic cancer cells and nerve cells, which could provide a new theoretical model for the mechanism research of pancreatic cancer nerve metastasis.

周围神经侵犯（PNI）是导致胰腺癌早期转移和术后复发的主要原因之一。肿瘤微环境细胞之间“信号交互作用”理论是PNI的分子基础。然而，作为信号交互作用的始动因素，肿瘤细胞通过何种机制将信息传递至神经细胞却仍不为所知。本课题组在前期的研究中发现胰腺癌细胞Hh信号通路对外泌体MALAT-1有正向调控作用，并通过基因芯片、生物信息学分析和体外实验研究相结合的方法，建立了MALAT-1与相应的MiRNAs以及重要的趋化因子CX3CL1和GDNF的调控关系。因此，推理在胰腺癌中Hh信号通路上调MALAT-1的转录，并通过exosome介导运输，启动胰腺癌细胞与神经细胞的信号交互作用，调控PNI的发生。本课题组拟以胰腺癌细胞中“Hh-外泌体MALAT-1”途径对神经细胞的调控为核心，深入研究胰腺癌细胞与神经细胞的交互作用机制，为胰腺癌神经转移的机制提供新的理论模式。

胰腺癌的周围神经侵犯（PNI）是其重要的生物学特性，研究证实胰腺癌细胞和神经组织之间存在着“相互吸引”的现象，其分子基础为肿瘤微环境细胞间“信号交互作用”理论。本研究发现胰腺癌（CFPAC-1）细胞中Hh-Gli1信号通路被激活后，其下游的靶基因不仅影响胰腺癌细胞的功能，还能够通过外泌体途径作用于神经细胞（DRGs），使其发生趋化及轴突出芽现象。基于上述研究基础，我们进一步通过高通量测序、生物信息学分析及体内外实验研究相结合的方法，筛选出与神经损伤修复相关的重要因子VGF及Unc5c，并建立了外泌体从CFPAC-1向DRGs细胞传递信号过程中“Gli1-circRNA-miRNA”的重要分子机制。本课题的完成，不仅为深入研究胰腺癌细胞与神经细胞的交互作用机制奠定了理论基础，还为临床治疗胰腺癌相关PNI提供了治疗新靶点。