Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA.
Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA 92037, USA; Laboratory for Advanced Medicine Research, SHIONOGI & CO., LTD., 3-1-1, Futaba-cho, Toyonaka, 561-0825, Japan.
Cancer Cell. 2020 Aug 10;38(2):247-262.e11. doi: 10.1016/j.ccell.2020.05.018. Epub 2020 Jun 25.
Oxidative stress plays a critical role in liver tissue damage and in hepatocellular carcinoma (HCC) initiation and progression. However, the mechanisms that regulate autophagy and metabolic reprogramming during reactive oxygen species (ROS) generation, and how ROS promote tumorigenesis, still need to be fully understood. We show that protein kinase C (PKC) λ/ι loss in hepatocytes promotes autophagy and oxidative phosphorylation. This results in ROS generation, which through NRF2 drives HCC through cell-autonomous and non-autonomous mechanisms. Although PKCλ/ι promotes tumorigenesis in oncogene-driven cancer models, emerging evidence demonstrate that it is a tumor suppressor in more complex carcinogenic processes. Consistently, PKCλ/ι levels negatively correlate with HCC histological tumor grade, establishing this kinase as a tumor suppressor in liver cancer.
氧化应激在肝组织损伤以及肝癌（HCC）的发生和进展中起着关键作用。然而，调节活性氧（ROS）生成过程中自噬和代谢重编程的机制，以及 ROS 如何促进肿瘤发生，仍需要充分理解。我们发现，肝细胞中蛋白激酶 C（PKC）λ/ι 的缺失会促进自噬和氧化磷酸化。这导致 ROS 的产生，ROS 通过 NRF2 通过细胞自主和非自主机制驱动 HCC。虽然 PKCλ/ι 在癌基因驱动的癌症模型中促进肿瘤发生，但新出现的证据表明，它在更复杂的致癌过程中是一种肿瘤抑制因子。一致地，PKCλ/ι 的水平与 HCC 的组织学肿瘤分级呈负相关，这表明该激酶在肝癌中是一种肿瘤抑制因子。
