Xin Wang1, Tingbo Ye1,2, Bingqian Xue1, Meihua Yang3, Rui Li1, Xiaohui Xu1, Xin Zeng1, Na Tian1, Liming Bao4, Yi Huang5. 1. Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, No. 136 Zhongshan Erd Road, Yuzhong District, Chongqing, 400014, China. 2. The Third People's Hospital of Chengdu, Chengdu, 610031, China. 3. Department of Neurosurgery, Xinqiao Hospital, Army Medical University, Chongqing, 400037, China. 4. Department of Pathology, University of Colorado School of Medicine, Aurora, CO, 80045, USA. 5. Chongqing Key Laboratory of Child Infection and Immunity, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, No. 136 Zhongshan Erd Road, Yuzhong District, Chongqing, 400014, China. yihuang828@foxmail.com.
Abstract
BACKGROUND: NRF2, a prime target of cellular defense against oxidative stress, has shown a dark side profile in cancer progression. GRIM-19, an essential subunit of the mitochondrial MRC complex I, was recently identified as a suppressive role in tumorigenesis of human gastric cancer (GC). However, little information is available on the role of GRIM-19 and its cross-talk with NRF2 in GC metastasis. METHODS: Online GC database was used to investigate DNA methylation and survival outcomes of GRIM-19. CRISPR/Cas9 lentivirus-mediated gene editing, metastasis mice models and pharmacological intervention were applied to investigate the role of GRIM-19 deficiency in GC metastasis. Quantitative RT-PCR, FACS, Western blot, IHC, IF and reporter gene assay were performed to explore underlying mechanisms. RESULTS: Low GRIM-19 is correlated with poor survival outcome of GC patients while DNA hypermethylation is associated with GRIM-19 downregulation. GRIM-19 deficiency facilitates GC metastasis and triggers aberrant oxidative stress as well as ROS-dependent NRF2-HO-1 activation. Experimental interventions of specific ROS, NRF2 or HO-1 inhibitor significantly abrogate GRIM-19 deficiency-driven GC metastasis in vitro and in vivo. Moreover, HO-1 inhibition not only reverses GRIM-19 deficiency-driven NRF2 activation, but also feedback blocks NRF2 activator-induced NRF2 signaling, resulting in decreased metastasis-associated genes. CONCLUSIONS: Our data suggest that GRIM-19 deficiency accelerates GC metastasis through the oncogenic ROS-NRF2-HO-1 axis via a positive-feedback NRF2-HO-1 loop. Therefore, this study not only offers novel insights into the role of oncogenic NRF2 in tumor progression, but also provides new strategies to alleviate the dark side of NRF2 by targeting HO-1.
BACKGROUND:NRF2, a prime target of cellular defense against oxidative stress, has shown a dark side profile in cancer progression. GRIM-19, an essential subunit of the mitochondrial MRC complex I, was recently identified as a suppressive role in tumorigenesis of humangastric cancer (GC). However, little information is available on the role of GRIM-19 and its cross-talk with NRF2 in GC metastasis. METHODS: Online GC database was used to investigate DNA methylation and survival outcomes of GRIM-19. CRISPR/Cas9 lentivirus-mediated gene editing, metastasis mice models and pharmacological intervention were applied to investigate the role of GRIM-19 deficiency in GC metastasis. Quantitative RT-PCR, FACS, Western blot, IHC, IF and reporter gene assay were performed to explore underlying mechanisms. RESULTS: Low GRIM-19 is correlated with poor survival outcome of GC patients while DNA hypermethylation is associated with GRIM-19 downregulation. GRIM-19 deficiency facilitates GC metastasis and triggers aberrant oxidative stress as well as ROS-dependent NRF2-HO-1 activation. Experimental interventions of specific ROS, NRF2 or HO-1 inhibitor significantly abrogate GRIM-19 deficiency-driven GC metastasis in vitro and in vivo. Moreover, HO-1 inhibition not only reverses GRIM-19 deficiency-driven NRF2 activation, but also feedback blocks NRF2 activator-induced NRF2 signaling, resulting in decreased metastasis-associated genes. CONCLUSIONS: Our data suggest that GRIM-19 deficiency accelerates GC metastasis through the oncogenic ROS-NRF2-HO-1 axis via a positive-feedback NRF2-HO-1 loop. Therefore, this study not only offers novel insights into the role of oncogenic NRF2 in tumor progression, but also provides new strategies to alleviate the dark side of NRF2 by targeting HO-1.
Authors: Gina M DeNicola; Florian A Karreth; Timothy J Humpton; Aarthi Gopinathan; Cong Wei; Kristopher Frese; Dipti Mangal; Kenneth H Yu; Charles J Yeo; Eric S Calhoun; Francesca Scrimieri; Jordan M Winter; Ralph H Hruban; Christine Iacobuzio-Donahue; Scott E Kern; Ian A Blair; David A Tuveson Journal: Nature Date: 2011-07-06 Impact factor: 49.962
Authors: Elena Piskounova; Michalis Agathocleous; Malea M Murphy; Zeping Hu; Sara E Huddlestun; Zhiyu Zhao; A Marilyn Leitch; Timothy M Johnson; Ralph J DeBerardinis; Sean J Morrison Journal: Nature Date: 2015-10-14 Impact factor: 49.962