Department of Pharmaceutical Sciences, University of Perugia, Italy.
Translational Research Laboratory, Arcispedale S. Maria Nuova-IRCCS, Reggio Emilia, Italy.
Transl Res. 2018 Mar;193:54-71. doi: 10.1016/j.trsl.2017.11.007. Epub 2017 Nov 29.
Deregulation of autophagy is proposed to play a key pathogenic role in hepatocellular carcinoma (HCC), the most common primary malignancy of the liver and the third leading cause of cancer death. Autophagy is an evolutionarily conserved catabolic process activated to degrade and recycle cell's components. Under stress conditions, such as oxidative stress and nutrient deprivation, autophagy is an essential survival pathway that operates in harmony with other stress response pathways. These include the redox-sensitive transcription complex Nrf2-Keap1 that controls groups of genes with roles in detoxification and antioxidant processes, intermediary metabolism, and cell cycle regulation. Recently, a functional association between a dysfunctional autophagy and Nrf2 pathway activation has been identified in HCC. This appears to occur through the physical interaction of the autophagy adaptor p62 with the Nrf2 inhibitor Keap1, thus leading to increased stabilization and transcriptional activity of Nrf2, a key event in reprogramming metabolic and stress response pathways of proliferating hepatocarcinoma cells. These emerging molecular mechanisms and the therapeutic perspective of targeting Nrf2-p62 interaction in HCC are discussed in this paper along with the prognostic value of autophagy in this type of cancer.
自噬的失调被认为在肝细胞癌（HCC）中起着关键的致病作用，HCC 是肝脏最常见的原发性恶性肿瘤，也是癌症死亡的第三大主要原因。自噬是一种进化上保守的分解代谢过程，可激活以降解和回收细胞成分。在应激条件下，如氧化应激和营养缺乏，自噬是一种与其他应激反应途径协同作用的必要生存途径。这些途径包括氧化还原敏感转录复合物 Nrf2-Keap1，它控制着一组具有解毒和抗氧化过程、中间代谢和细胞周期调节作用的基因。最近，在 HCC 中已经确定了功能失调的自噬与 Nrf2 途径激活之间的功能关联。这似乎是通过自噬衔接蛋白 p62 与 Nrf2 抑制剂 Keap1 的物理相互作用发生的，从而导致 Nrf2 的稳定性和转录活性增加，这是增殖性肝癌细胞代谢和应激反应途径重新编程的关键事件。本文讨论了这些新出现的分子机制以及在 HCC 中靶向 Nrf2-p62 相互作用的治疗观点，以及自噬在这种癌症中的预后价值。
