Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma

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 aggress...

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Published in:Liver international 2024-08
Main Authors: Xu, Kaiyu, Kessler, Annika, Nichetti, Federico, Hoffmeister-Wittmann, Paula, Scherr, Anna-Lena, Nader, Luisa, Kelmendi, Eblina, Schmitt, Nathalie, Schwab, Maximilian, García-Beccaria, María, Sobol, Benjamin, Nieto, Osama Azzam, Isele, Hanna, Gärtner, Ulrike, Vaquero-Siguero, Nuria, Volk, Julia, Korell, Felix, Mock, Andreas, Heide, Danijela, Ramadori, Pierluigi, Lenoir, Bénédicte, Albrecht, Thomas, Hüllein, Jennifer, Jäger, Dirk, Fröhling, Stefan, Springfeld, Christoph, Jackstadt, Rene, Heikenwälder, Mathias, Dill, Michael T, Roessler, Stephanie, Goeppert, Benjamin, Köhler, Bruno C
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Language:English
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Summary: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.BACKGROUND AND AIMSCholangiocarcinoma (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.METHODSHuman 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 s
ISSN:1478-3231
1478-3231
DOI:10.1111/liv.16069