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dc.creatorHoffmeister-Wittmann, P. (Paula)-
dc.creatorMock, A. (Andreas)-
dc.creatorNichetti, F. (Federico)-
dc.creatorKorell, F. (Felix)-
dc.creatorHeilig, C.E. (Christoph E.)-
dc.creatorScherr, A.L. (Anna Lena)-
dc.creatorGünther, M. (Michael)-
dc.creatorAlbrecht, T. (Thomas)-
dc.creatorKelmendi, E. (Eblina)-
dc.creatorXu, K. (Kaiyu)-
dc.creatorNader, L. (Luisa)-
dc.creatorKessler, A. (Annika)-
dc.creatorSchmitt, N. (Nathalie)-
dc.creatorFritzsche, S. (Sarah)-
dc.creatorWeiler, S. (Sofia)-
dc.creatorSobol, B. (Benjamin)-
dc.creatorStenzinger, A. (Albrecht)-
dc.creatorBoeck, S. (Stefan)-
dc.creatorWestphalen, C.B. (Christoph B.)-
dc.creatorSchulze-Osthoff, K. (Klaus)-
dc.creatorTrojan, J. (Jörg)-
dc.creatorKindler, T. (Thomas)-
dc.creatorWeichert, W. (Wilko)-
dc.creatorSpiekermann, K. (Karsten)-
dc.creatorBitzer, M. (Michael)-
dc.creatorFolprecht, G. (Gunnar)-
dc.creatorIllert, A.L. (Anna L.)-
dc.creatorBoerries, M. (Melanie)-
dc.creatorKlauschen, F. (Frederick)-
dc.creatorOchsenreiter, S. (Sebastian)-
dc.creatorSiveke, J. (Jens)-
dc.creatorBauer, S. (Sebastian)-
dc.creatorGlimm, H. (Hanno)-
dc.creatorBrors, B. (Benedikt)-
dc.creatorHüllein, J. (Jennifer)-
dc.creatorHübschmann, D. (Daniel)-
dc.creatorUhrig, S. (Sebastian)-
dc.creatorHorak, P. (Peter)-
dc.creatorKreutzfeld, S. (Simon)-
dc.creatorBanales, J.M. (Jesús M.)-
dc.creatorSpringfeld, C. (Christoph)-
dc.creatorJäger, D. (Dirk)-
dc.creatorSchirmacher, P. (Peter)-
dc.creatorRoessler, S. (Stephanie)-
dc.creatorOrmanns, S. (Steffen)-
dc.creatorGoeppert, B. (Benjamin)-
dc.creatorFröhling, S. (Stefan)-
dc.creatorKöhler, B.C. (Bruno C.)-
dc.identifier.citationHoffmeister-Wittmann, P.; Mock, A.; Nichetti, F.; et al. "Bcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma". Liver International. 42 (12), 2022, 2855 - 2870es
dc.description.abstractIntrahepatic, perihilar, and distal cholangiocarcinoma (iCCA, pCCA, dCCA) are highly malignant tumours with increasing mortality rates due to therapy resistances. Among the mechanisms mediating resistance, overexpression of anti-apoptotic Bcl-2 proteins (Bcl-2, Bcl-x(L), Mcl-1) is particularly important. In this study, we investigated whether antiapoptotic protein patterns are prognostically relevant and potential therapeutic targets in CCA. Bcl-2 proteins were analysed in a pan-cancer cohort from the NCT/DKFZ/DKTK MASTER registry trial (n = 1140, CCA n = 72) via RNA-sequencing and transcriptome-based protein activity interference revealing high ranks of CCA for Bcl-x(L) and Mcl-1. Expression of Bcl-x(L), Mcl-1, and Bcl-2 was assessed in human CCA tissue and cell lines compared with cholangiocytes by immunohistochemistry, immunoblotting, and quantitative-RT-PCR. Immunohistochemistry confirmed the upregulation of Bcl-x(L) and Mcl-1 in iCCA tissues. Cell death of CCA cell lines upon treatemnt with specific small molecule inhibitors of Bcl-x(L) (Wehi-539), of Mcl-1 (S63845), and Bcl-2 (ABT-199), either alone, in combination with each other or together with chemotherapeutics was assessed by flow cytometry. Targeting Bcl-x(L) induced cell death and augmented the effect of chemotherapy in CCA cells. Combined inhibition of Bcl-x(L) and Mcl-1 led to a synergistic increase in cell death in CCA cell lines. Correlation between Bcl-2 protein expression and survival was analysed within three independent patient cohorts from cancer centers in Germany comprising 656 CCA cases indicating a prognostic value of Bcl-x(L) in CCA depending on the CCA subtype. Collectively, these observations identify Bcl-x(L) as a key protein in cell death resistance of CCA and may pave the way for clinical application.-
dc.description.sponsorshipDKTK Joint Funding Program; NCT Molecular Precision Oncology Program; “Fundación Científica de la Asociación Española Contra el Cáncer”; Department of Health of the Basque Country, Grant/ Award Number: 2017111010; CIBERehd (ISCIII); Miguel Servet Program, Grant/ Award Number: CPII19/00008; Spanish Carlos III Health Institute (ISCIII), Grant/Award Number: PI21/00922 and PI18/01075; Abbvie; PSC Partners Seeking A Cure Foundation; Deutsche Krebshilfe, Grant/Award Number: 70113593 and 70113922; Deutsche Forschungsgemeinschaft, Grant/Award Number: KO-5205/3–1, KO-5205/1–1 and 314905040 – SFB/TRR 209-
dc.titleBcl-x(L) as prognostic marker and potential therapeutic target in cholangiocarcinoma-
dc.description.noteThis is an open access article under the terms of the Creative Commons Attribution-NonCommercial License,-
dadun.citation.publicationNameLiver International-

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