RIPK1 抑制依赖于 TRAF2 的肝癌通路。
RIPK1 Suppresses a TRAF2-Dependent Pathway to Liver Cancer.
机构信息
Department of Medicine III, RWTH Aachen University, 52074 Aachen, Germany; Division of Gastroenterology, Hepatology and Hepatobiliary Oncology, RWTH Aachen University, 52074 Aachen, Germany.
Department of Dermatology and Allergology, RWTH Aachen University, 52074 Aachen, Germany.
出版信息
Cancer Cell. 2017 Jan 9;31(1):94-109. doi: 10.1016/j.ccell.2016.11.009. Epub 2016 Dec 22.
Receptor-interacting protein kinase 1 (RIPK1) represents an essential signaling node in cell death and inflammation. Ablation of Ripk1 in liver parenchymal cells (LPC) did not cause a spontaneous phenotype, but led to tumor necrosis factor (TNF)-dependent hepatocyte apoptosis and liver injury without affecting inducible nuclear factor κB (NF-κB) activation. Loss of Ripk1 induced the TNF-dependent proteasomal degradation of the E3-ligase, TNF receptor-associated factor 2 (TRAF2), in a kinase-independent manner, thereby activating caspase-8. Moreover, loss of both Ripk1 and Traf2 in LPC not only resulted in caspase-8 hyperactivation but also impaired NF-κB activation, promoting the spontaneous development of hepatocellular carcinoma. In line, low RIPK1 and TRAF2 expression in human HCCs was associated with an unfavorable prognosis, suggesting that RIPK1 collaborates with TRAF2 to inhibit murine and human hepatocarcinogenesis.
受体相互作用蛋白激酶 1（RIPK1）是细胞死亡和炎症的一个重要信号节点。在肝实质细胞（LPC）中敲除 Ripk1 不会导致自发表型，但会导致肿瘤坏死因子（TNF）依赖性肝细胞凋亡和肝损伤，而不影响诱导型核因子 κB（NF-κB）的激活。Ripk1 的缺失以激酶非依赖性的方式诱导 TNF 依赖性 E3 连接酶，TNF 受体相关因子 2（TRAF2 的蛋白水解降解，从而激活半胱天冬酶-8。此外，LPC 中 Ripk1 和 Traf2 的缺失不仅导致 caspase-8 的过度激活，而且还损害了 NF-κB 的激活，促进了肝细胞癌的自发发展。与此一致，人 HCC 中低表达 RIPK1 和 TRAF2 与预后不良相关，表明 RIPK1 与 TRAF2 合作抑制鼠和人肝癌的发生。
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