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000292352 1001_ $$aXu, Kaiyu$$b0
000292352 245__ $$aLymphotoxin beta-activated LTBR/NIK/RELB axis drives proliferation in cholangiocarcinoma.
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000292352 500__ $$a#EA:B340# / 2024 Nov;44(11):2950-2963 / DKFZ-ZMBH Alliance
000292352 520__ $$aCholangiocarcinoma (CCA) is an aggressive malignancy arising from the intrahepatic (iCCA) or extrahepatic (eCCA) bile ducts with poor prognosis and limited treatment options. Prior evidence highlighted a significant contribution of the non-canonical NF-κB signalling pathway in initiation and aggressiveness of different tumour types. Lymphotoxin-β (LTβ) stimulates the NF-κB-inducing kinase (NIK), resulting in the activation of the transcription factor RelB. However, the functional contribution of the non-canonical NF-κB signalling pathway via the LTβ/NIK/RelB axis in CCA carcinogenesis and progression has not been established.Human CCA-derived cell lines and organoids were examined to determine the expression of NF-κB pathway components upon activation or inhibition. Proliferation and cell death were analysed using real-time impedance measurement and flow cytometry. Immunoblot, qRT-PCR, RNA sequencing and in situ hybridization were employed to analyse gene and protein expression. Four in vivo models of iCCA were used to probe the activation and regulation of the non-canonical NF-κB pathway.Exposure to LTα1/β2 activates the LTβ/NIK/RelB axis and promotes proliferation in CCA. Inhibition of NIK with the small molecule inhibitor B022 efficiently suppresses RelB expression in patient-derived CCA organoids and nuclear co-translocation of RelB and p52 stimulated by LTα1/β2 in CCA cell lines. In murine CCA, RelB expression is significantly increased and LTβ is the predominant ligand of the non-canonical NF-κB signalling pathway.Our study confirms that the non-canonical NF-κB axis LTβ/NIK/RelB drives cholangiocarcinogenesis and represents a candidate therapeutic target.
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000292352 650_7 $$2Other$$aLTB
000292352 650_7 $$2Other$$aNF‐κB
000292352 650_7 $$2Other$$aNIK
000292352 650_7 $$2Other$$aRelB
000292352 650_7 $$2Other$$acholangiocarcinoma
000292352 650_7 $$2Other$$asmall molecule inhibitor B022
000292352 7001_ $$aKessler, Annika$$b1
000292352 7001_ $$0P:(DE-He78)05009f364d8e161b5a650d482b9e8a1e$$aNichetti, Federico$$b2$$eFirst author
000292352 7001_ $$aHoffmeister-Wittmann, Paula$$b3
000292352 7001_ $$aScherr, Anna-Lena$$b4
000292352 7001_ $$aNader, Luisa$$b5
000292352 7001_ $$aKelmendi, Eblina$$b6
000292352 7001_ $$aSchmitt, Nathalie$$b7
000292352 7001_ $$aSchwab, Maximilian$$b8
000292352 7001_ $$0P:(DE-HGF)0$$aGarcía-Beccaria, María$$b9
000292352 7001_ $$aSobol, Benjamin$$b10
000292352 7001_ $$aNieto, Osama Azzam$$b11
000292352 7001_ $$aIsele, Hanna$$b12
000292352 7001_ $$aGärtner, Ulrike$$b13
000292352 7001_ $$0P:(DE-HGF)0$$aVaquero-Siguero, Nuria$$b14
000292352 7001_ $$0P:(DE-He78)aaa8eb8347aa4d45f1ac2d9968eaa8e4$$aVolk, Julia$$b15
000292352 7001_ $$0P:(DE-HGF)0$$aKorell, Felix$$b16
000292352 7001_ $$0P:(DE-He78)8f7c3bc1451193551c2458d93222536a$$aMock, Andreas$$b17
000292352 7001_ $$0P:(DE-He78)92c93319837b4b915db8393795faf0b6$$aHeide, Danijela$$b18
000292352 7001_ $$0P:(DE-He78)6e985c345eb4618b127cf0fe1bff1522$$aRamadori, Pierluigi$$b19
000292352 7001_ $$0P:(DE-He78)4671d97058e8d2ddb314e6be4de0c403$$aLenoir, Bénédicte$$b20
000292352 7001_ $$00000-0002-2234-0909$$aAlbrecht, Thomas$$b21
000292352 7001_ $$0P:(DE-He78)c9be4ab60d1090c3d315a2ca6905e9ea$$aHüllein, Jennifer$$b22
000292352 7001_ $$0P:(DE-He78)ed0321409c9cde20b380ae663dbcefd1$$aJäger, Dirk$$b23$$udkfz
000292352 7001_ $$0P:(DE-He78)f0144d171d26dbedb67c9db1df35629d$$aFröhling, Stefan$$b24
000292352 7001_ $$aSpringfeld, Christoph$$b25
000292352 7001_ $$0P:(DE-He78)5da14633266cbfff7746cf529c110673$$aJackstadt, Rene-Filip$$b26
000292352 7001_ $$0P:(DE-He78)66ed2d4ec9bc11d29b87ac006adf85e5$$aHeikenwälder, Mathias$$b27
000292352 7001_ $$0P:(DE-He78)54a6641a6c26ddc49cc754740e90b438$$aDill, Michael$$b28
000292352 7001_ $$aRoessler, Stephanie$$b29
000292352 7001_ $$aGoeppert, Benjamin$$b30
000292352 7001_ $$0P:(DE-He78)21ee1e660035cae35605a39903143096$$aKöhler, Bruno C$$b31
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