BRG1通过ZFP91介导NIK/NF-κB信号轴促进胆囊癌早期转移的分子机制研究

胆囊癌因极早转移而预后很差。上皮间质转化（EMT）是上皮肿瘤侵袭转移的关键细胞学行为，涉及大量基因的异常转录，与染色质重塑机制紊乱有关。我们发现染色质重塑复合体SWI/SNF关键亚基BRG1在发生早期转移的胆囊癌中高表达并提示更差预后。体外实验证实BRG1明显促进胆囊癌细胞EMT。RNA-seq提示NF-κB通路相关基因在BRG1高表达组织中升高，而Wnt、Hippo、Notch等变化不明显。NF-κB主要激活细胞因子、炎症介质，是炎症相关肿瘤（如胆囊癌）的重要促进因子。进一步发现NF-κB的经典激活途径并没有活化，相反非经典途径关键因子NIK、p52等明显升高。该途径受ZFP91的调控，而ZFP91则可能是BRG1的靶基因。我们推测BRG1/ZFP91/NIK/NF-κB信号轴在胆囊癌EMT中至关重要，本研究将验证该假设，揭示胆囊癌独特的EMT机制，为合理干预其早期转移提供理论支持。

Gallbladder cancer has a poor prognosis mainly due to early intrahepatic or lymph node metastasis. Epithelial-mesenchymal transformation (EMT) is a key cytological factor for the invasive and metastatic process of epithelial tumors. A large number of genes are abnormally transcribed during EMT, which is closely correlated with the dysfunction of the chromatin remodeling complex. We found that BRG1, a key subunit of SWI/SNF complex, was overexpressed in metastatic gallbladder cancer, especially in those with early metastasis. High-BRG1 expression was associated with a poorer prognosis. BRG1 could significantly promote EMT and metastasis in gallbladder cancer cells. RNA-seq showed that NF-κB pathway related genes were significantly increased in patients with high-BRG1 expression, while Wnt, Hippo, Notch and other pathway-related genes were not significantly changed. NF-κB pathway mainly activates cytokines and inflammatory mediators and is an important promoter of the inflammation-related tumors such as gallbladder cancer. We further found the canonical pathway of NF-κB was not activated during the process, whereas the noncanonical pathway related genes, such as NIK and p52 were significantly increased. This pathway was regulated by ZFP91, which might be a target gene of BRG1. Thus, we speculated that the BRG1/ZFP91/NIK/NF-κB pathway was crucial in the EMT and metastasis of gallbladder cancer. This study will verify this hypothesis and reveal the unique EMT mechanism of gallbladder cancer, providing a theoretical support for the intervention of early metastasis of gallbladder cancer.