Department of Pathology and Laboratory Medicine, Weill Cornell Medicine , New York, NY, USA.
Autophagy. 2020 Oct;16(10):1915-1917. doi: 10.1080/15548627.2020.1797290. Epub 2020 Jul 25.
Hepatocellular carcinoma (HCC) is the consequence of chronic liver damage caused by the excessive generation of reactive oxygen species (ROS). To mitigate the deleterious effects of ROS, cells activate the transcription factor NFE2L2/NRF2, which is constitutively degraded through its partner KEAP1. The inactivation of KEAP1 by ROS results in the upregulation of NFE2L2, which leads to the upregulation of critical detoxifying molecules that serve to keep ROS at tolerable levels in order to maintain cell viability. It is thought that this mechanism allows cells to accumulate mutations, which together with the additional pro-tumorigenic and pro-survival effects of NFE2L2 activation, promote cancer initiation and progression. Germane to this phenomenon is macroautophagy/autophagy, which under homeostatic conditions has also been proposed to serve as a detoxifying mechanism by clearing up toxic aggregates and damaged organelles. Our recent data establish a new paradigm for the role that autophagy plays in HCC development.
肝细胞癌（HCC）是由活性氧（ROS）过度产生引起的慢性肝损伤的结果。为了减轻 ROS 的有害影响，细胞激活转录因子 NFE2L2/NRF2，该转录因子通过其伴侣 KEAP1 持续降解。ROS 使 KEAP1 失活导致 NFE2L2 的上调，这导致关键解毒分子的上调，这些分子有助于将 ROS 维持在可耐受水平以维持细胞活力。人们认为，这种机制允许细胞积累突变，再加上 NFE2L2 激活的额外的促肿瘤发生和生存效应，促进癌症的发生和发展。与此相关的是巨自噬/自噬，在稳态条件下，自噬也被提出作为一种解毒机制，通过清除有毒聚集体和受损的细胞器。我们最近的数据为自噬在 HCC 发展中的作用建立了一个新的范例。
