肝细胞癌（HCC）是最常见的原发性肝脏肿瘤，全球发病率不断增加。 HCC 是一种异质性恶性肿瘤，通常发生在慢性损伤的肝脏中。核因子 kappa B (NF-κB) 信号网络由规范分支和非规范分支组成。文献记载了 HCC 中典型 NF-κB 的激活。然而，非经典 NF-κB 及其下游效应子的功能和临床相关作用尚未确定。对四个人类 HCC 队列（总数 = 1,462）和四个小鼠 HCC 模型进行了 NF-κB 信号成分的表达和定位评估和活化配体。在体外，测量了 NF-κB 信号传导、增殖和细胞死亡，证明了通过 NIK 激活的 RELB 具有促增殖作用。在体内，淋巴毒素β (LTβ) 被确定为 RELB 激活的主要诱导剂。重要的是，与对照组相比，小鼠 HCC 模型中肝细胞特异性 RELB 敲除导致发病率降低，最大肿瘤直径也降低。在计算机上，使用推断的蛋白质活性和基因集富集分析 (GSEA) 在 TCGA HCC 队列上验证了 RELB 活性和 RELB 定向转录组学。在 RELB 活性 HCC 中，介导增殖的途径显着激活。与 RELA 相比，非典型 RELB 表达的核富集以与病因无关的方式识别预后不良的患者。此外，RELB 激活与恶性特征转移和复发相关。这项研究证明了肝癌发生中 LTβ/LTβR/RELB 轴的激活与预后相关、与病因无关且跨物种一致。这些观察结果可能对 HCC 具有广泛的影响，包括可能的临床利用。版权所有 © 2023 美国肝病研究协会。

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.Copyright © 2023 American Association for the Study of Liver Diseases.