NF-κB信号通路反馈性泛素化网络失控促食管非可控炎症诱导恶性转化的分子机制

The strength and duration of nuclear factor-kappa B (NF-κB) signaling is tightly controlled at diverse levels under physiological condition. It has been demonstrated that negative feedback mechanisms plays important roles in inhibiting the NF-κB signaling pathway and quelling inflammatory responses. However, the mechanisms and critical factors involved in the induction of constutively activated NF-κB signaling pathway and nonresolving inflammation and their effects on cell transformation (including immortalization and genomic instability) remain largely unclear. Previously, we have reported that the dysregulation of ubiquitination /deubiquitination network could sustain the NF-κB signaling pathway and induce nonresolving inflammation (JCI, Cell Res). Recently, by integrating the results obtained from bioinformatics analysis and biological experiments, we have found that ①deregulation of multiple negative regulators of NF-κB signaling pathway ( such as RNF121、USP2、miR-548k), mediated by genomic amplification and/or deletion, resulted in constutive activation of NF-κB signaling pathway and nonresolving inflammation, which further ②transcriptional upregulated onco-protein TBL1XR1 that increased the expression of genes related to cell immortalization, so extending the cellular lifespan, and③transcriptional upregulated onco-protein AEG-1 that reduced the expression levels of DNA repair genes which led to genomic instability. Therefore, the current project utilized in vivo and in vitro experimental systems in addition to data from clinical samples to investigate the mechanisms by which dysregulation of feed-back ubiquitination network of NF-κB pathway-mediated nonresolving inflammation induced esophageal cells transformation.

机体可通过多层面负反馈调节机制而可控性抑制NF-κB炎症通路激活的时间和强度，及时平息炎症。但NF-κB信号通路负反馈调节失控诱导持续性炎症并促发恶性转化(包括早期转化,基因组不稳定)的关键节点及调控机制，目前仍未阐明。前期我们多项研究揭示：反馈性泛素化/去泛素化网络失调可维持NF-κB通路持续性激活并诱发非可控炎症(JCI,Cell Res)。近期预实验我们发现：①多个反馈性泛素化网络调节分子(如RNF121、USP2、miR-548k等)因基因组扩增/缺失而表达异常从而高度激活NF-κB炎症通路，并可转录②上调TBL1XR1而促进多个早期转化基因表达及延长正常细胞寿命，③上调AEG-1而抑制多个DNA修复基因而导致基因组不稳定；最终促使细胞恶性转化。本项目将承前启后，深层次解析NF-κB信号通路反馈性泛素化网络失控诱导食管非可控炎症及恶性转化的分子机制，为肿瘤诊断治疗提供新的靶位点。

以肿瘤NF-κB信号通路的调控机制为研究切入点，不仅为肿瘤发生发展增添新的理论依据，还为肿瘤治疗药物的研发提供重要的靶位点。① 我们证明DNA损伤可促进TRIM37入核单泛素化NEMO蛋白而DNA损伤激活的NF-κB信号通路，并揭示了食管癌化疗耐药的分子机制 (Cancer Res. 2018; 78(22):6399-6412)。② 我们研究发现miR-892b可调控NF-κB信号通路多个正调控关键因子的表达，从而促进了NF-κB信号通路的泛素化及磷酸化水平，而维持了肿瘤炎性的持续性 (Cancer Res. 2016; 76:1101-11). ③ 我们研究显示TRIM3可泛素化降解Impotin α3及ACTN4上调，进而维持了肿瘤NF-κB炎性通路的持续性 (Oncogene. 2018 Dec 12)。④ 我们发现RNA结合蛋白RBMS3可通过抑制miR-126-5p所激活的WNT/β-catenin信号通路而促进肿瘤对化疗药物顺铂的敏感性(Clin Cancer Res. 2018 Oct 2)。⑤ 我们发现HOXC10可促进蛋白精氨酸甲基转移酶5（PRMT5）和WD重复结构域5（WDR5）在VEGFA启动子上结合并上调VEGFA的表达，为肿瘤抗血管生成治疗的潜在靶点。 (Theranostics. 2018; 8(18):5143-5158)。⑥ 我们研究结果显示炎症微环境可上调miR-455-3p而维持了Wnt/β-catenin及TGF-β signaling信号通路非可控性，为NF-κB信号通路促肿瘤恶性发展增添了科学根据（Mol Cancer. 2017;16(1):106)。项目完成期间，共发表(共同)通讯作者文章11篇，9篇> 5分，其中1篇 > 10分。