表观遗传调控与化学致癌密切相关。我们前期发现IFI44L受DNA甲基化调控导致表达沉默是化学致肺癌过程中的重要分子事件，但作用机制尚不明确。预实验发现：该基因过表达显著抑制肺癌细胞生长和迁移并促进其凋亡，而抑制STAT1后明显降低其抑癌作用；该基因与STAT1及下游XAF1、TRAIL、OAS表达呈显著正相关；进一步分析提示IFI44L与STAT1存在相互作用。由此推测：IFI44L是一个新的甲基化调控的抑癌基因，可能通过调控STAT1通路介导的下游关键基因的表达参与化学致肺癌过程。本项目拟利用基因敲除动物、化学致肺癌模型及细胞恶性转化模型并结合临床肺癌标本，通过基因过表达和干扰、干预等实验，全面揭示IFI44L基因的表观调控和主要生物学功能及在化学致肺癌过程中的作用，阐明该基因调控STAT1通路及下游基因表达的作用及分子机制，为寻找环境化学物致肺癌的早期生物标志物和预防策略提供科学依据。

Epigenetic regulation is closely related to chemical carcinogenesis. Our previous studies showed that DNA hypermethylation accounting for IFI44L gene silencing is an important molecular biology event during the process of chemical-induced lung cancer. However, the relevant role and molecular mechanism was unclear. Preliminary experiments showed that IFI44L overexpression could significantly inhibit lung cancer cell growth and migration, and promote cell apoptosis. The tumor suppressor role of IFI44L was markedly decreased after the inhibition of STAT1. IFI44L expression was significantly positively correlated with the expression of STAT1 and the downstream key genes XAF1, TRAIL, and OAS. Further analysis suggests that IFI44L could interact with STAT1. Therefore, we speculate that IFI44L gene is a novel tumor suppressor gene regulated by DNA methylation, which may participate in the whole process of chemical-induced lung cancer through regulating STAT1 mediated downstream gene expression. This project is planned to reveal the epigenetic regulation and main biological functions of IFI44L gene and its role during the process of chemical-induced lung cancer through gene overexpression/knockdown and intervention experiments on gene knock-out animal model, chemical-induced lung cancer model and cell malignant transformation model, clinical lung cancer samples. Additionally, we will elucidate the role and molecular mechanism of IFI44L gene in regulating STAT1 pathway and downstream gene expression. This project may provide scientific basis for looking for early biomarkers and prevention strategies of lung cancer induced by environmental chemicals.