Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma
Background and Aims 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 in...
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| Main Authors: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
November 2024
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| In: |
Liver international
Year: 2024, Volume: 44, Issue: 11, Pages: 2950-2963 |
| ISSN: | 1478-3231 |
| DOI: | 10.1111/liv.16069 |
| Online Access: | Verlag, kostenfrei, Volltext: https://doi.org/10.1111/liv.16069 Verlag, kostenfrei, Volltext: https://onlinelibrary.wiley.com/doi/abs/10.1111/liv.16069 
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| Author Notes: | Kaiyu Xu, Annika Kessler, Federico Nichetti, Paula Hoffmeister-Wittmann, Anna-Lena Scherr, Luisa Nader, Eblina Kelmendi, Nathalie Schmitt, Maximilian Schwab, María García-Beccaria, Benjamin Sobol, Osama Azzam Nieto, Hanna Isele, Ulrike Gärtner, Nuria Vaquero-Siguero, Julia Volk, Felix Korell, Andreas Mock, Danijela Heide, Pierluigi Ramadori, Bénédicte Lenoir, Thomas Albrecht, Jennifer Hüllein, Dirk Jäger, Stefan Fröhling, Christoph Springfeld, Rene Jackstadt, Mathias Heikenwälder, Michael T. Dill, Stephanie Roessler, Benjamin Goeppert, Bruno C. Köhler |
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| 245 | 1 | 0 | |a Lymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma |c Kaiyu Xu, Annika Kessler, Federico Nichetti, Paula Hoffmeister-Wittmann, Anna-Lena Scherr, Luisa Nader, Eblina Kelmendi, Nathalie Schmitt, Maximilian Schwab, María García-Beccaria, Benjamin Sobol, Osama Azzam Nieto, Hanna Isele, Ulrike Gärtner, Nuria Vaquero-Siguero, Julia Volk, Felix Korell, Andreas Mock, Danijela Heide, Pierluigi Ramadori, Bénédicte Lenoir, Thomas Albrecht, Jennifer Hüllein, Dirk Jäger, Stefan Fröhling, Christoph Springfeld, Rene Jackstadt, Mathias Heikenwälder, Michael T. Dill, Stephanie Roessler, Benjamin Goeppert, Bruno C. Köhler |
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| 520 | |a Background and Aims 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. Methods 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. Results 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. Conclusions Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target. | ||
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