Fig. 6 KHK-A–mediated p62 S28 phosphorylation promotes hepatocellular tumorigenesis and is associated with clinical aggressiveness of human HCC. KHK-A–mediated.

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Fig. 6 KHK-A–mediated p62 S28 phosphorylation promotes hepatocellular tumorigenesis and is associated with clinical aggressiveness of human HCC. KHK-A–mediated p62 S28 phosphorylation promotes hepatocellular tumorigenesis and is associated with clinical aggressiveness of human HCC. (A) Huh7 (1 × 106) cells with or without knock-in of KHK-A S80A (top) or p62 S28A (bottom) expression were intrahepatically injected into athymic nude mice (n = 7 per group). The mice were euthanized and examined for tumor growth 28 days after injection. The arrows point to the tumors. Tumor volumes were calculated (right). Data represent the means ± SD of seven mice. **P < 0.01 by a two-tailed Student’s t test. (B) IHC analyses of tumor tissues were performed with an anti-Ki67 antibody. Ki67-positive cells were quantified in 10 microscope fields. **P < 0.01 by a two-tailed Student’s t test. (C and D) IHC analyses of xenograft tumors from nude mice were performed with the indicated antibodies. (E) IHC staining of 30 human HCC and matched nontumor tissue samples was performed with the indicated antibodies. Representative photos of stains of two cases are shown. (F) IHC staining of 90 human HCC specimens was performed with the indicated antibodies. Representative images from the staining of four different specimens are shown. (G) Kaplan-Meier plots of the overall survival rates in human HCC specimens (n = 90) in groups with high (staining score, 4 to 8) and low (staining score, 0 to 3) expression of KHK-A pS80, p62 pS28, and KHK-C. The P values were calculated using the log-rank test. (H) The mechanism underlying differentiated responses of normal hepatocytes and HCC cells to oxidative stress. Oxidative stress results in AMPK-mediated phosphorylation of KHK-A S80, primarily expressed in HCC cells, but not of KHK-C, primarily expressed in normal hepatocytes. S80-phosphorylated KHK-A acts as a protein kinase and phosphorylates p62 S28, resulting in p62 oligomerization, p62 and Keap1 aggregation, and nuclear translocation and activation of Nrf2, which lead to counteracting ROS production, maintaining tumor cell survival, and promoting HCC development. In contrast, normal hepatocytes, lacking KHK-A–mediated antioxidative response, have high levels of ROS production and increased apoptosis. Ub, ubiquitin. Daqian Xu et al. Sci Adv 2019;5:eaav4570 Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).