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@ARTICLE{Scherr:285129,
      author       = {A.-L. Scherr and L. Nader and K. Xu and C. Elssner and D.
                      A. Ridder and F. Nichetti and M. Mastel$^*$ and S. Fritzsche
                      and E. Kelmendi and N. Schmitt and P. Hoffmeister-Wittmann
                      and S. M. E. Weiler and F. Korell$^*$ and T. Albrecht and M.
                      Schwab and H. Isele and A. Kessler and J. Hüllein and A.
                      Seretny$^*$ and L. Ye and T. Urbanik and S. Welte and A.-L.
                      Leblond and C. Heilig$^*$ and M. Rahbari$^*$ and A. Ali$^*$
                      and S. U. Gallage$^*$ and B. M. A. Lenoir$^*$ and N.
                      Wilhelm$^*$ and U. Gärtner and S. J. Ogrodnik$^*$ and C.
                      Springfeld and D. F. Tschaharganeh$^*$ and S. Fröhling$^*$
                      and T. Longerich and H. Schulze-Bergkamen and D. Jäger$^*$
                      and L. Brandl and P. Schirmacher and B. K. Straub and A.
                      Weber and E. N. De Toni and B. Goeppert and M.
                      Heikenwälder$^*$ and R.-F. Jackstadt$^*$ and S. Roessler
                      and K. Breuhahn and B. C. Köhler$^*$},
      title        = {{E}tiology-independent activation of the
                      {LT}β-{LT}β{R}-{RELB} axis drives aggressiveness and
                      predicts poor prognosis in {H}epatocellular carcinoma.},
      journal      = {Hepatology},
      volume       = {80},
      number       = {2},
      issn         = {0270-9139},
      address      = {[Alphen aan den Rijn]},
      publisher    = {Wolters Kluwer Health},
      reportid     = {DKFZ-2023-02253},
      pages        = {278-294},
      year         = {2024},
      note         = {2024 Aug 1;80(2):278-294 / DKFZ-ZMBH Alliance},
      abstract     = {Hepatocellular carcinoma (HCC) is the most common primary
                      liver tumor with an increasing incidence worldwide. HCC is a
                      heterogeneous malignancy and develops usually in a
                      chronically injured liver. The nuclear factor kappa B
                      (NF-κB) signaling network consists of a canonical and a
                      non-canonical branch. An activation of canonical NF-κB in
                      HCC is documented. However, a functional and clinically
                      relevant role of non-canonical NF-κB and its downstream
                      effectors is not established.Four human HCC cohorts (total
                      n=1,462) and four mouse HCC models were assessed for
                      expression and localization of NF-κB signaling components
                      and activating ligands. In vitro, NF-κB signaling,
                      proliferation and cell death were measured, proving a
                      pro-proliferative role of RELB activated via NIK. In vivo,
                      Lymphotoxin beta (LTβ) was identified as predominant
                      inducer of RELB activation. Importantly, hepatocyte-specific
                      RELB knockout in a murine HCC model led to a lower incidence
                      compared to controls and lower maximal tumor diameters. In
                      silico, RELB activity and RELB directed transcriptomics were
                      validated on the TCGA HCC cohort using inferred protein
                      activity and Gene Set Enrichment Analysis (GSEA). In
                      RELB-active HCC, pathways mediating proliferation were
                      significantly activated. In contrast to RELA, nuclear
                      enrichment of non-canonical RELB expression identified
                      patients with a poor prognosis in an etiology-independent
                      manner. Moreover, RELB activation was associated with
                      malignant features metastasis and recurrence.This study
                      demonstrates a prognostically relevant, etiology-independent
                      and cross-species consistent activation of a LTβ/LTβR/RELB
                      axis in hepatocarcinogenesis. These observations may harbor
                      broad implications for HCC, including possible clinical
                      exploitation.},
      cin          = {A013 / HD01 / F190 / B340 / F180 / D120 / B063},
      ddc          = {610},
      cid          = {I:(DE-He78)A013-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)F190-20160331 / I:(DE-He78)B340-20160331 /
                      I:(DE-He78)F180-20160331 / I:(DE-He78)D120-20160331 /
                      I:(DE-He78)B063-20160331},
      pnm          = {316 - Infektionen, Entzündung und Krebs (POF4-316)},
      pid          = {G:(DE-HGF)POF4-316},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:37916976},
      doi          = {10.1097/HEP.0000000000000657},
      url          = {https://inrepo02.dkfz.de/record/285129},
}