Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.

中文翻译：

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Caspase-8在触发和感知与增殖相关的DNA损伤中的双重作用，这是决定肝癌发展的关键因素。

伴随的肝细胞凋亡和再生是易患肝细胞癌（HCC）的慢性肝病（CLD）的标志。在这里，我们通过增殖和复制相关的DNA损伤将caspase-8依赖的细胞凋亡机制性地联系到肝癌的发展。在任何肿瘤改变发生之前，可在CLD中检测到与增殖相关的复制压力，DNA损伤和遗传不稳定性。肝细胞凋亡的累积水平决定并预测随后的肝癌发生。与增殖相关的DNA损伤可通过一种复合物来感知，该复合物包含caspase-8，FADD，c-FLIP和RIPK1的激酶依赖性功能。该平台需要caspase-8的非凋亡功能，但不需要caspase-3或caspase-8裂解。