NLRP3炎症小体通过促进NK细胞功能抑制肝癌转移及机制研究

Recurrence and metastasis of liver cancer is the leading cause of high mortality in hepatocellular carcinoma (HCC). It has been confirmed that metastatic spread occurs at the very early stage of tumor, and whether early metastatic tumor cells could escape the immune surveillance of NK cells and develop into new tumor nodules is an important factor for tumor metastasis. IL-1β and IL-18 induced by NLRP3 inflammasome activation promote NK cell tumoricidal activity. In the previous study, we have found that NLRP3-/- mice had exacerbated HCC metastatic growth than WT mice, and the expression of NLRP3 in Kupffer cells in carcinoma is much lower than that in paracarcinoma tissues. These results are consistent with clinical statistics, which all suggest that NLRP3 inflammasome activation may play an important role in inhibiting intrahepatic metastasis of HCC. No relevant report has been reported so far. In this study, NLRP3 inflammasome related components will be inhibited to further determine the relationship between NLRP3 inflammasome and HCC metastasis; adoptive cell transfer and immunofluorescence techniques will be used to explore the source of NLRP3 inflammasome and related cytokines; Rag2-/- mice and mice depleted of NK cells will be used to investigate the role of innate immune system and NK cells in NLRP3 inflammasome-induced control of metastatic dissemination, and the molecular mechanism. This research will provide novel therapeutic strategy for HCC metastasis.

肝癌复发转移是导致肝癌高死亡率的最主要原因。已证实，转移在肿瘤早期即发生，且早期转移的肿瘤细胞能否继续发展形成肿瘤结节与NK细胞介导的免疫监视作用密切相关，NLRP3炎症小体活化产生的IL-1β和IL-18可促进NK细胞的杀伤活性。申请人已研究发现，NLRP3-/-小鼠肝癌肝内转移程度较WT小鼠明显增加，且肝癌组织Kupffer细胞中NLRP3表达水平较癌旁组织明显降低。该结果与临床统计数据相一致，提示NLRP3炎症小体活化在抑制肝癌肝内转移过程中可能发挥重要作用。迄今未见相关报道。本研究拟通过抑制NLRP3炎症小体相关分子，进一步确定其与肝癌转移关系；利用过继转输和免疫荧光技术确定NLRP3炎症小体及相关细胞因子来源；利用Rag2-/-小鼠和清除NK细胞的小鼠探究固有免疫系统和NK细胞在NLRP3炎症小体抑制肝癌转移中的作用，并阐明其分子学机制，以期为临床预防和治疗肝癌转移提供新思路。

肝癌复发转移是导致肝癌高死亡率的最主要原因。已证实，肿瘤早期即发生转移，且伴随着多种分子表达水平的改变。NLRP3分子是存在于胞浆中的一类模式识别受体，形成的炎症小体在活化后可产生IL-1β和IL-18等细胞因子，参与多种病理生理过程。然而，NLRP3分子在肝癌转移过程中的作用尚不得而知。本研究发现，NLRP3分子在肝癌组织中低表达；NLRP3分子的高表达与肝癌转移呈负相关；NLRP3分子缺失小鼠更易发生肝癌转移；肝癌细胞中过表达NLRP3分子可显著抑制肝癌转移程度，且这种抑制作用与上皮间充质转化过程密切相关。本研究通过阐明NLRP3分子在肝癌转移中的作用及分子机制，以期为临床预防和治疗肝癌转移提供新思路。