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Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in HCC

Background and Aims: - HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch. Activation of canonical NF-...

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Main Authors: Scherr, Anna-Lena (Author) , Nader, Luisa (Author) , Xu, Kaiyu (Author) , Elssner, Christin (Author) , Ridder, Dirk A. (Author) , Nichetti, Federico (Author) , Mastel, Manuel (Author) , Fritzsche, Sarah (Author) , Kelmendi, Eblina (Author) , Schmitt, Nathalie (Author) , Hoffmeister-Wittmann, Paula (Author) , Weiler, Sofia Maria Elisabeth (Author) , Korell, Felix (Author) , Albrecht, Thomas (Author) , Schwab, Maximilian (Author) , Isele, Hanna (Author) , Keßler, Annika (Author) , Hüllein, Jennifer (Author) , Seretny, Agnieszka (Author) , Ye, Liangtao (Author) , Urbanik, Toni (Author) , Welte, Stefan (Author) , Leblond, Anne-Laure (Author) , Heilig, Christoph E. (Author) , Rahbari, Mohammad (Author) , Ali, Sheikh Adnan (Author) , Gallage, Suchira (Author) , Lenoir, Bénédicte (Author) , Wilhelm, Nina (Author) , Gärtner, Ulrike (Author) , Ogrodnik, Simon J. (Author) , Springfeld, Christoph (Author) , Tschaharganeh, Darjus-Felix (Author) , Fröhling, Stefan (Author) , Longerich, Thomas (Author) , Schulze-Bergkamen, Henning (Author) , Jäger, Dirk (Author) , Brandl, Lydia (Author) , Schirmacher, Peter (Author) , Straub, Beate Katharina (Author) , Weber, Achim (Author) , De Toni, Enrico N. (Author) , Goeppert, Benjamin (Author) , Heikenwalder, Mathias (Author) , Jackstadt, René-Filip (Author) , Rössler, Stephanie (Author) , Breuhahn, Kai (Author) , Köhler, Bruno Christian (Author)
Format: Article (Journal)
Language:English
Published: August 2024
In: Hepatology
Year: 2024, Volume: 80, Issue: 2, Pages: 278-294
ISSN:1527-3350
DOI:10.1097/HEP.0000000000000657
Online Access:Verlag, lizenzpflichtig, Volltext: https://doi.org/10.1097/HEP.0000000000000657
Verlag, lizenzpflichtig, Volltext: https://journals.lww.com/hep/fulltext/9900/etiology_independent_activation_of_the.631.aspx
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Author Notes:Anna-Lena Scherr, Luisa Nader, Kaiyu Xu, Christin Elssner, Dirk A. Ridder, Federico Nichetti, Manuel Mastel, Sarah Fritzsche, Eblina Kelmendi, Nathalie Schmitt, Paula Hoffmeister-Wittmann, Sofia M.E. Weiler, Felix Korell, Thomas Albrecht, Maximilian Schwab, Hanna Isele, Annika Kessler, Jennifer Hüllein, Agnieszka Seretny, Liangtao Ye, Toni Urbanik, Stefan Welte, Anne-Laure Leblond, Christoph E. Heilig, Mohammad Rahbari, Adnan Ali, Suchira Gallage, Bénédicte Lenoir, Nina Wilhelm, Ulrike Gärtner, Simon J. Ogrodnik, Christoph Springfeld, Darjus Tschaharganeh, Stefan Fröhling, Thomas Longerich, Henning Schulze-Bergkamen, Dirk Jäger, Lydia Brandl, Peter Schirmacher, Beate K. Straub, Achim Weber, Enrico N. De Toni, Benjamin Goeppert, Mathias Heikenwalder, Rene Jackstadt, Stephanie Roessler, Kai Breuhahn, Bruno C. Köhler
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Summary:Background and Aims: - HCC is the most common primary liver tumor, with an increasing incidence worldwide. HCC is a heterogeneous malignancy and usually develops in a chronically injured liver. The NF-κB signaling network consists of a canonical and a noncanonical branch. Activation of canonical NF-κB in HCC is documented. However, a functional and clinically relevant role of noncanonical NF-κB and its downstream effectors is not established. - Approach and Results: - Fur human HCC cohorts (total n = 1462) and 4 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 v-rel avian reticuloendotheliosis viral oncogene homolog B (RELB) activated by means of NF-κB-inducing kinase. In vivo, lymphotoxin beta was identified as the 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 The Cancer Genome Atlas HCC cohort using inferred protein activity and Gene Set Enrichment Analysis. In RELB-active HCC, pathways mediating proliferation were significantly activated. In contrast to v-rel avian reticuloendotheliosis viral oncogene homolog A, nuclear enrichment of noncanonical RELB expression identified patients with a poor prognosis in an etiology-independent manner. Moreover, RELB activation was associated with malignant features metastasis and recurrence. - Conclusions: - This study demonstrates a prognostically relevant, etiology-independent, and cross-species consistent activation of a lymphotoxin beta/LTβR/RELB axis in hepatocarcinogenesis. These observations may harbor broad implications for HCC, including possible clinical exploitation. Export
Item Description:Gesehen am 19.02.2024
Physical Description:Online Resource
ISSN:1527-3350
DOI:10.1097/HEP.0000000000000657

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