胆管癌（CCA）是一种源自肝内（iCCA）或肝外（eCCA）胆管的侵袭性恶性肿瘤，预后不良，治疗选择有限。先前的证据强调了非典型 NF-κB 信号通路在不同肿瘤类型的发生和侵袭中的重要贡献。淋巴毒素-β (LTβ) 刺激 NF-κB 诱导激酶 (NIK)，从而激活转录因子 RelB。然而，通过 LTβ/NIK/RelB 轴的非经典 NF-κB 信号通路在 CCA 致癌和进展中的功能贡献尚未确定。对人类 CCA 衍生的细胞系和类器官进行了检查以确定 NF-的表达。激活或抑制时的 κB 通路成分。使用实时阻抗测量和流式细胞术分析增殖和细胞死亡。采用免疫印迹、qRT-PCR、RNA 测序和原位杂交来分析基因和蛋白质表达。使用四种 iCCA 体内模型来探测非经典 NF-κB 通路的激活和调节。暴露于 LTα1/β2 会激活 LTβ/NIK/RelB 轴并促进 CCA 中的增殖。用小分子抑制剂 B022 抑制 NIK 可有效抑制患者来源的 CCA 类器官中的 RelB 表达以及 CCA 细胞系中 LTα1/β2 刺激的 RelB 和 p52 的核共转位。在小鼠 CCA 中，RelB 表达显着增加，LTβ 是非经典 NF-κB 信号通路的主要配体。我们的研究证实，非经典 NF-κB 轴 LTβ/NIK/RelB 驱动胆管癌发生，是一种候选治疗方法target.© 2024 作者。约翰·威利 (John Wiley) 出版的《肝脏国际》

Cholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non-canonical NF-κB signalling pathway via the LTβ/NIK/RelB axis in CCA carcinogenesis and progression has not been established.Human CCA-derived cell lines and organoids were examined to determine the expression of NF-κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real-time impedance measurement and flow cytometry. Immunoblot, qRT-PCR, RNA sequencing and in situ hybridization were employed to analyse gene and protein expression. Four in vivo models of iCCA were used to probe the activation and regulation of the non-canonical NF-κB pathway.Exposure to LTα1/β2 activates the LTβ/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient-derived CCA organoids and nuclear co-translocation of RelB and p52 stimulated by LTα1/β2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTβ is the predominant ligand of the non-canonical NF-κB signalling pathway.Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target.© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.