Buchumschlag

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-...

Ausführliche Beschreibung

Gespeichert in:
Bibliographische Detailangaben
Hauptverfasser: Scherr, Anna-Lena (VerfasserIn) , Nader, Luisa (VerfasserIn) , Xu, Kaiyu (VerfasserIn) , Elssner, Christin (VerfasserIn) , Ridder, Dirk A. (VerfasserIn) , Nichetti, Federico (VerfasserIn) , Mastel, Manuel (VerfasserIn) , Fritzsche, Sarah (VerfasserIn) , Kelmendi, Eblina (VerfasserIn) , Schmitt, Nathalie (VerfasserIn) , Hoffmeister-Wittmann, Paula (VerfasserIn) , Weiler, Sofia Maria Elisabeth (VerfasserIn) , Korell, Felix (VerfasserIn) , Albrecht, Thomas (VerfasserIn) , Schwab, Maximilian (VerfasserIn) , Isele, Hanna (VerfasserIn) , Keßler, Annika (VerfasserIn) , Hüllein, Jennifer (VerfasserIn) , Seretny, Agnieszka (VerfasserIn) , Ye, Liangtao (VerfasserIn) , Urbanik, Toni (VerfasserIn) , Welte, Stefan (VerfasserIn) , Leblond, Anne-Laure (VerfasserIn) , Heilig, Christoph E. (VerfasserIn) , Rahbari, Mohammad (VerfasserIn) , Ali, Sheikh Adnan (VerfasserIn) , Gallage, Suchira (VerfasserIn) , Lenoir, Bénédicte (VerfasserIn) , Wilhelm, Nina (VerfasserIn) , Gärtner, Ulrike (VerfasserIn) , Ogrodnik, Simon J. (VerfasserIn) , Springfeld, Christoph (VerfasserIn) , Tschaharganeh, Darjus-Felix (VerfasserIn) , Fröhling, Stefan (VerfasserIn) , Longerich, Thomas (VerfasserIn) , Schulze-Bergkamen, Henning (VerfasserIn) , Jäger, Dirk (VerfasserIn) , Brandl, Lydia (VerfasserIn) , Schirmacher, Peter (VerfasserIn) , Straub, Beate Katharina (VerfasserIn) , Weber, Achim (VerfasserIn) , De Toni, Enrico N. (VerfasserIn) , Goeppert, Benjamin (VerfasserIn) , Heikenwalder, Mathias (VerfasserIn) , Jackstadt, René-Filip (VerfasserIn) , Rössler, Stephanie (VerfasserIn) , Breuhahn, Kai (VerfasserIn) , Köhler, Bruno Christian (VerfasserIn)
Dokumenttyp: Article (Journal)
Sprache:Englisch
Veröffentlicht: August 2024
In: Hepatology
Year: 2024, Jahrgang: 80, Heft: 2, Pages: 278-294
ISSN:1527-3350
DOI:10.1097/HEP.0000000000000657
Online-Zugang: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
Volltext
Verfasserangaben: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
Beschreibung
Zusammenfassung: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
Beschreibung:Gesehen am 19.02.2024
Beschreibung:Online Resource
ISSN:1527-3350
DOI:10.1097/HEP.0000000000000657

Ähnliche Einträge