Author information

¹Department of Medical Oncology, National Center for Tumor Diseases (NCT) Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.

²Department of General Pathology, University Hospital Mainz, Mainz, Germany.

³Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale Dei Tumori, Milan, Italy.

⁴Computational Oncology, Molecular Diagnostics Program, National Center for Tumor Diseases (NCT) and German Cancer Research Center (DKFZ), Heidelberg, Germany.

⁵Heidelberg Institute for Stem Cell Technology and Experimental Medicine (HI-STEM gGmbH), Heidelberg, Germany.

⁶Cancer Progression and Metastasis Group, German Cancer Research Center (DKFZ) and DKFZ-ZMBH Alliance, Heidelberg, Germany.

⁷Institute of Pathology, University Hospital Heidelberg, Heidelberg, Germany.

⁸Department of Radiooncology, University Hospital Heidelberg, Heidelberg, Germany.

⁹German Cancer Consortium (DKTK), Heidelberg, Germany.

¹⁰Department of Medicine V, University Hospital Heidelberg, Heidelberg, Germany.

¹¹Liver Cancer Center Heidelberg, University Hospital Heidelberg, Heidelberg, Germany.

¹²Helmholtz-University Group "Cell Plasticity and Epigenetic Remodeling", German Cancer Research Center (DKFZ), Heidelberg, Germany.

¹³Department of Internal Medicine II, Klinikum Grosshadern, Ludwig-Maximilians-University of Munich.

¹⁴Department of Pathology and Molecular Pathology, University and University Hospital Zurich, Zurich, Switzerland.

¹⁵Department of Translational Medical Oncology, NCT Heidelberg and German Cancer Research Center (DKFZ), Heidelberg, Germany.

¹⁶Division of Chronic Inflammation and Cancer, German Cancer Research Center Heidelberg (DKFZ), Heidelberg, Germany.

¹⁷Clinical Cooperation Unit "Applied Tumor Immunity", German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.

¹⁸Interfaculty Biomedical Research Facility, University of Heidelberg, Heidelberg, Germany.

¹⁹Division of Cancer Genome Research, German Cancer Research Center (DKFZ), Heidelberg, Germany.

²⁰Department of Internal Medicine II, Marien-Hospital, Wesel, Germany.

²¹Institute of Pathology, Medical Faculty, Ludwig-Maximilians-University, Munich, Germany.

²²The M3 Research Center, University Clinic Tübingen (UKT), Medical faculty, Tübingen, Germany.

Abstract

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: Four 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.