TY  - JOUR
AU  - Scherr, Anna-Lena
AU  - Nader, Luisa
AU  - Xu, Kaiyu
AU  - Elssner, Christin
AU  - Ridder, Dirk A
AU  - Nichetti, Federico
AU  - Mastel, Manuel
AU  - Fritzsche, Sarah
AU  - Kelmendi, Eblina
AU  - Schmitt, Nathalie
AU  - Hoffmeister-Wittmann, Paula
AU  - Weiler, Sofia M E
AU  - Korell, Felix
AU  - Albrecht, Thomas
AU  - Schwab, Maximilian
AU  - Isele, Hanna
AU  - Kessler, Annika
AU  - Hüllein, Jennifer
AU  - Seretny, Agnieszka
AU  - Ye, Liangtao
AU  - Urbanik, Toni
AU  - Welte, Stefan
AU  - Leblond, Anne-Laure
AU  - Heilig, Christoph
AU  - Rahbari, Mohammad
AU  - Ali, Adnan
AU  - Gallage, Suchira Upeksha
AU  - Lenoir, Benedicte Marie Anne
AU  - Wilhelm, Nina
AU  - Gärtner, Ulrike
AU  - Ogrodnik, Simon John
AU  - Springfeld, Christoph
AU  - Tschaharganeh, Darjus Felix
AU  - Fröhling, Stefan
AU  - Longerich, Thomas
AU  - Schulze-Bergkamen, Henning
AU  - Jäger, Dirk
AU  - Brandl, Lydia
AU  - Schirmacher, Peter
AU  - Straub, Beate K
AU  - Weber, Achim
AU  - De Toni, Enrico N
AU  - Goeppert, Benjamin
AU  - Heikenwälder, Mathias
AU  - Jackstadt, Rene-Filip
AU  - Roessler, Stephanie
AU  - Breuhahn, Kai
AU  - Köhler, Bruno Christian
TI  - Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in Hepatocellular carcinoma.
JO  - Hepatology
VL  - 80
IS  - 2
SN  - 0270-9139
CY  - [Alphen aan den Rijn]
PB  - Wolters Kluwer Health
M1  - DKFZ-2023-02253
SP  - 278-294
PY  - 2024
N1  - 2024 Aug 1;80(2):278-294 / DKFZ-ZMBH Alliance
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - pmid:37916976
DO  - DOI:10.1097/HEP.0000000000000657
UR  - https://inrepo02.dkfz.de/record/285129
ER  -