Department of General Surgery, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
Institute of Physiological Chemistry, University of Ulm, Ulm, Germany.
Hepatology. 2016 May;63(5):1592-607. doi: 10.1002/hep.28435. Epub 2016 Mar 4.
Chronic hepatitis B virus (HBV) infection remains the most common risk factor for hepatocellular carcinoma (HCC). Efficient suppression of HBV viremia and necroinflammation as a result of nucleos(t)ide analogue treatment is able to reduce HCC incidence; nevertheless, hepatocarcinogenesis can occur in the absence of active hepatitis, correlating with high HBV surface antigen (HBsAg) levels. Nuclear factor κB (NF-κB) is a central player in chronic inflammation and HCC development. However, in the absence of severe chronic inflammation, the role of NF-κB signaling in HCC development remains elusive. As a model of hepatocarcinogenesis driven by accumulation of HBV envelope polypeptides, HBsAg transgenic mice, which show no HBV-specific immune response, were crossed to animals with hepatocyte-specific inhibition of canonical NF-κB signaling. We detected prolonged, severe endoplasmic reticulum stress already at 20 weeks of age in NF-κB-deficient hepatocytes of HBsAg-expressing mice. The unfolded protein response regulator binding immunoglobulin protein/78-kDa glucose-regulated protein was down-regulated, activating transcription factor 6, and eIF2α were activated with subsequent overexpression of CCAAT/enhancer binding protein homologous protein. Notably, immune cell infiltrates and liver transaminases were unchanged. However, as a result of this increased cellular stress, insufficient hepatocyte proliferation due to G1 /S-phase cell cycle arrest with overexpression of p27 and emergence of ductular reactions was detected. This culminated in increased DNA damage already at 20 weeks of age and finally led to 100% HCC incidence due to NF-κB inhibition.
The role of canonical NF-κB signaling in HCC development depends on the mode of liver damage; in the case of HBsAg-driven hepatocarcinogenesis, NF-κB in hepatocytes acts as a critical tumor suppressor by augmenting the endoplasmic reticulum stress response.
慢性乙型肝炎病毒（HBV）感染仍然是肝细胞癌（HCC）最常见的危险因素。核苷（酸）类似物治疗导致的 HBV 病毒血症和坏死性炎症的有效抑制能够降低 HCC 的发病率；然而，在没有活动性肝炎的情况下也会发生肝癌发生，这与高 HBV 表面抗原（HBsAg）水平相关。核因子 κB（NF-κB）是慢性炎症和 HCC 发展的核心参与者。然而，在没有严重慢性炎症的情况下，NF-κB 信号在 HCC 发展中的作用仍不清楚。作为由 HBV 包膜多肽积累驱动的肝癌发生模型，HBsAg 转基因小鼠表现出无 HBV 特异性免疫反应，与具有肝细胞特异性抑制经典 NF-κB 信号的动物杂交。我们在表达 HBsAg 的小鼠的 NF-κB 缺陷型肝细胞中已经检测到 20 周龄时就存在持续的、严重的内质网应激。未折叠蛋白反应调节剂结合免疫球蛋白蛋白/78kDa 葡萄糖调节蛋白被下调，激活转录因子 6，eIF2α 被激活，随后 CCAAT/增强子结合蛋白同源蛋白过表达。值得注意的是，免疫细胞浸润和肝转氨酶没有变化。然而，由于这种细胞应激增加，由于 G1/S 期细胞周期阻滞和 p27 过表达导致的肝细胞增殖不足，以及胆管反应的出现被检测到。这在 20 周龄时就导致了 DNA 损伤的增加，最终由于 NF-κB 抑制导致 100%的 HCC 发生率。
经典 NF-κB 信号在 HCC 发展中的作用取决于肝损伤的模式；在 HBsAg 驱动的肝癌发生中，NF-κB 在肝细胞中作为一种关键的肿瘤抑制因子，通过增强内质网应激反应发挥作用。
