AIM2调控IL-1β介导NF-κB通路促进食管鳞癌增殖及转移

Inflammatory microenvironment plays an important role in the progression of esophageal squamous cell cancer (ESCC). Although inflammatory cytokines had been proved to promote tumor proliferation and metastasis through a variety of pathways, their expression and secretion mechanisms in ESCC were still not illuminated. In previous experiments, we had found AIM2 expression was significantly up-regulated in ESCC tumor tissues. AIM2 could suppress cell apoptosis, promote epithelial-mesenchymal transition (EMT), and then increase the proliferative, invasive and migrated ability in ESCC cell lines. Meanwhile, AIM2 could also up-regulate the expression and secretion of cytokine IL-1β, and activate the NF-κB pathway. Therefore, we inferred that AIM2 might regulate the IL-1β expression and secretion to control the NF-κB pathway activation, regulate gene expressions relating to apoptosis and EMT, and then affect the proliferative, invasive and migrated ability of ESCC cell lines. In this study, we plan to explore the role of AIM2 in regulating ESCC developments through IL-1β/NF-κB signaling pathway, by employing techniques including in vivo/ in vitro experiments, luciferase reporter gene, electrophoretic mobility shift assay, and the usage of NF-κB pathway blocker, IL-1β antibody and IL-1β receptor blocker. The study would elucidate the molecular mechanism of AIM2 as an oncogene in ESCC development, and preliminarily provide a novel target for ESCC treatments.

炎症微环境在食管鳞癌发生发展中发挥着重要作用。微环境中的炎性因子可通过多种途径促进肿瘤细胞增殖及转移，但其在食管鳞癌中的表达及分泌调控机制尚不明确。我们在预实验中发现：AIM2在食管鳞癌中过表达，能通过抑制细胞凋亡、促进细胞上皮间充质转化，增强食管鳞癌增殖及侵袭迁移能力。同时，AIM2还可上调炎症介质IL-1β的表达及分泌，并激活NF-κB信号通路。因此我们推测，AIM2可能调控IL-1β的表达与分泌，后者通过影响NF-κB通路的活化水平，进一步调控凋亡及EMT相关基因等的表达，影响食管鳞癌的增殖及转移。本课题拟进一步通过体内外实验、荧光素酶报告基因、EMSA等方法，结合NF-κB通路阻滞剂、IL-1β抗体及受体阻滞剂等，观察AIM2/IL-1β/NF-κB信号转导通路对食管鳞癌生长转移的调控作用，从而阐明AIM2在食管鳞癌中发挥促癌作用的分子机制，为食管鳞癌的治疗提供新理论及新靶点。

微环境中的炎性因子可通过多种途径促进肿瘤细胞增殖及转移。既往文献报道AIM2可通过炎性复合体通路，介导IL-1β等炎症因子的成熟释放，但其在食管鳞癌炎症微环境形成中的作用尚不明确。我们前期利用基因表达谱芯片技术，发现食管鳞癌中炎症相关基因AIM2及IL1B均显著上调，并且通过体外细胞实验及体内小鼠模型，证实了AIM2表达水平影响食管鳞癌的增殖及侵袭转移能力，而这些变化分别与细胞凋亡及上皮间质转化密切相关。进一步的，我们发现AIM2可影响IL-1β的表达及分泌水平，以及NF-κB蛋白的磷酸化水平，并通过双荧光素酶报告基因实验证实了AIM2对NF-κB信号通路的激活作用。最后通过加入NF-κB信号通路阻滞剂及IL-1β受体阻滞剂，逆转AIM2在食管鳞癌中的促癌作用，进而有效的证明了AIM2通过上调IL-1β介导NF-κB通路激活，促进食管鳞癌增殖及转移这一机制，为食管鳞癌的治疗提供新理论及新靶点。