原癌基因AEG-1网络调控炎症非可控性及诱导恶性转化的分子机制

It has been demonstrated that negative feedback control mechanisms act to quell inflammatory responses and maintain homeostasis uder normal conditions. However, inflammation could sometimes escape this feedback suppression and become persistently activated. This nonresolving inflammation may lead to the malignant transformation of normal cells through the induction of genomic instability and cellular immortalization. The mechanisms and key factors involved in the induction of nonresolving inflammation and its effects on cell transformation remain unclear. Previously, we have reported that the oncogene, AEG-1, activates inflammatory signaling pathways and promotes tumor development. Recently, we have shown that the expression level of AEG-1 was significantly increased in nonresolving inflammatory cells, and the overexpression of AEG-1 could upregulate multiple miRNAs that maintain inflammation through the inhibition of negative feedback pathways. Additionally, they enhanced tumor development in nude mice. These data indicate that AEG-1 is a key molecular regulator of nonresolving inflammation. Furthermore, by integrating the results obtained from bioinformatic analysis and biological experiments, we found that AEG-1downregulated the expression levels of DNA repair genes which led to genomic instability, and increased the expression of genes related to cell immortalization, so extending the cellular lifespan. Therefore, the current project utilized in vivo and in vitro experimental systems in addition to data from clinical samples to investigate the biological role of AEG-1 in the regulation of nonresolving inflammation and malignant transformation.

机体在正常条件下可通过负反馈调控机制平息炎症反应而保持生理平衡。但炎症有时却可逃逸这些反馈抑制而表现出持续性激活(即非可控性炎症),甚至促使正常细胞恶性转化(包括早期转化,基因组不稳定)。然而非可控性炎症的形成及诱发恶性转化的关键节点及调控机制，目前仍很不清楚。前期我们已发表文章报道：原癌基因AEG-1可激活炎症信号通路并促进肿瘤的发生发展。近期预实验我们发现：①AEG-1在非可控性炎症细胞中显著增高，而高表达AEG-1又可上调多个miRNAs抑制炎症的负反馈通路而维持炎症的非可控性，并诱发高炎性肿瘤形成，这表明AEG-1是调控炎症非可控性的关键分子。进一步生物信息学及生物学实验结果显示：AEG-1还可②下调DNA修复基因而导致基因组不稳定；③上调永生化相关基因而延长正常细胞寿命。本项目将承前启后，深层次解析AEG-1调控炎症非可控性及诱发恶性转化的分子机制，为肿瘤诊断治疗提供新的靶位点。

机体在正常条件下可通过负反馈调控机制平息炎症反应而保持生理平衡。但炎症有时却可逃逸这些反馈抑制而表现出持续性激活(即非可控性炎症),甚至促使正常细胞恶性转化(包括早期转化,基因组不稳定)。然而非可控性炎症的形成及诱发恶性转化的关键节点及调控机制，目前仍很不清楚。前期我们已发表文章报道：原癌基因AEG-1 可激活炎症信号通路并促进肿瘤的发生发展。 进一步我们发现AEG-1调控一系列基因及miRNA参与到非可控性炎症诱导的肿瘤恶性发展中：①：我们研究发现miR-486可同时抑制TNIP1，TNIP2，TNIP3 及ITCH等去泛素化酶A20结合蛋白而维持NF-kB信号通路持续性激活（Cell Res， 通讯作者）。②．我们研究揭示了脂筏蛋白FLOT-1及其结合蛋白GOLPH3通过促进IKK信号体与TNF-α受体相结合而激活NF-κB信号通路的新机理（Clin.Cancer Res，通讯作者； J Pathol 共同通讯作者)。③ 我们新发现并验证了NF-kB结合蛋白AKIP1，为NF-kB信号通路促肿瘤恶性发展增添了科学根据（Cancer Res通讯作者； Oncogene通讯作者）.④我们证明了炎症可通过诱导miR-508而持续性激活PI3K/Akt信号通路，为NF-kB信号通路激活维持肿瘤生长自给自足增添了新的科学根据（Nat Communi， 共同通讯作者)。 项目研究期间共发表（共同）通讯/第一作者SCI文章7篇， 7篇> 5分，其中2篇〉10分。