Netrin-1激活的炎症体对肝癌“集体侵袭”的调控作用

Early invasion and metastasis is the main reason for recurrence and poor prognosis of hepatocellular carcinoma (HCC).Cancer cells acquire the ability to invade and metastasize as single cell process, which is mainly enabled by epithelial-mesenchymal transition(EMT).Recent studies have shown that cancer cells can invade surrounding tissue as collective invasion. Collective invasion is the new understanding of tumor recurrence and metastasis, which the mechanism needs to be further studied. Our previous studies showed that Netrin-1 promoted the activation of inflammasome, which could enable the invasion ability of HCC cells. Immunohistochemical studies showed that HCC cells invaded surrounding tissue as collective invasion. The expression of Netrin-1 in these HCC cells was increased. These findings suggest that the activation of inflammasome induced by Netrin-1 may promote collective invasion in HCC cells. On the basis of these, our next project will study how Netrin-1 activates inflammasome and promote collective invasion in HCC, signal transduction on membrane and downstream signal pathway of Netrin-1. 3D collagen I gels model and live imaging will be used to detect the affect of inhibition of Netrin-1 and destruction of lipid rafts on inflammasome and collective invasion. Study the mechanism of how Netrin-1 promotes collective invasion, investigate the role of collective invasion in early metastasis and recurrence of HCC and obtain potential intervention targets and theoretical support.

肝癌早期易发生侵袭转移，这是肝癌术后复发、疗效差的主要原因。癌细胞可通过上皮间质转化获得侵袭力以单细胞形式侵袭周围组织发生转移。最近研究发现，癌细胞还可以多细胞形式集体侵袭周围组织，这是对肿瘤侵袭转移的重新认识，其机制亟待研究。我们前期研究显示Netrin-1促进肝癌细胞炎症体的激活，炎症体激活可以增强肝癌细胞侵袭力；同时我们还发现肝癌细胞集体侵袭周围组织，Netrin-1在这些肝癌细胞中高表达。提示Netrin-1激活的炎症体可能在集体侵袭中发挥重要调节作用。本项目在此基础上，探讨Netrin-1及其受体在膜上脂筏中的信号传导及下游信号通路的激活。通过3DⅠ胶原凝胶模型、活体成像技术检测抑制Netrin-1和破坏脂筏对炎症体的激活及集体侵袭的影响。不同水平研究Netrin-1对肝癌集体侵袭的促进作用，阐明集体侵袭在肝癌早期转移中的机制，以期获得抑制肝癌早期转移潜在的干预靶点及理论支持。

肝癌早期易发生侵袭转移，这是肝癌术后复发、疗效差的主要原因。癌细胞可通过上皮间质转化获得侵袭力以单细胞形式侵袭周围组织发生转移。最近研究发现，癌细胞还能以多细胞形式集体侵袭周围组织，这是对肿瘤侵袭转移的重新认识，其机制亟待研究。Netrin-1是层黏连蛋白相关的分泌蛋白，参与调控神经轴突生长和肿瘤细胞的侵袭转移。本项目旨在研究netrin-1激活的炎性体在集体侵袭中的作用。我们的研究发现，netrin-1以及caspase-1在肝癌组织里高表达，netrin-1可以通过调节EMT促进肝癌细胞集体侵袭。Netrin-1通过相应受体DCC、UNC5H等促进caspase-1表达，进而激活下游靶基因BVES、NF-Kb以及EMT相关分子，进而促进肝癌细胞的侵袭。在肝癌的缺氧微环境中，netrin-1激活caspase-1促进了缺氧诱导的肝癌细胞转移。通过小鼠肺转移、肝转移模型及活体成像技术，抑制Netrin-1和caspase-1可抑制肝癌细胞集体侵袭。本项目通过不同水平的研究，发现netrin-1以及炎性体在肝癌转移里的重要作用，这对Netrin-1在调控肝癌细胞转移里的重要作用提出了进一步的认识，可能为抑制肝癌早期转移提供干预靶点。