Etiology-independent activation of the LTβ-LTβR-RELB axis drives aggressiveness and predicts poor prognosis in Hepatocellular carcinoma.
Journal
Hepatology (Baltimore, Md.)
ISSN: 1527-3350
Titre abrégé: Hepatology
Pays: United States
ID NLM: 8302946
Informations de publication
Date de publication:
02 Nov 2023
02 Nov 2023
Historique:
received:
21
12
2021
accepted:
21
09
2023
medline:
2
11
2023
pubmed:
2
11
2023
entrez:
2
11
2023
Statut:
aheadofprint
Résumé
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.
Sections du résumé
BACKGROUND AIMS
UNASSIGNED
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.
APPROACH RESULTS
UNASSIGNED
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.
CONCLUSIONS
CONCLUSIONS
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.
Identifiants
pubmed: 37916976
doi: 10.1097/HEP.0000000000000657
pii: 01515467-990000000-00631
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2023 American Association for the Study of Liver Diseases.