Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer
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Yi Huang1,*, Meihua Yang2,*, Huajian Hu3,*, Xiaodong Zhao1, Liming Bao1,4, Daochao Huang1,5, Lihua Song1,6, Yang Li1
1Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, China International Science and Technology Cooperation Base of Child Development and Critical Disorders, Chongqing 400014, PR China
2Department of Neurosurgery, Xinqiao Hospital of Third Military Medical University, Chongqing 400038, PR China
3Department of Gastroenterology, Children’s Hospital of Chongqing Medical University, Chongqing 400014, PR China
4Department of Pathology, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756, USA
5Animal Care Center, Children’s Hospital of Chongqing Medical University, Chongqing 400014, PR China
6Department of Gastroenterology, 416 Hospital of Nuclear Industry, Chengdu 610051, PR China
*These authors have contributed equally to this work
Yi Huang, e-mail: email@example.com
Keywords: GRIM-19, gastric cancer, chronic atrophic gastritis, clinical outcome, STAT3
Received: October 17, 2015 Accepted: April 11, 2016 Published: May 4, 2016
Aberrant STAT3 activation occurs in most human gastric cancers (GCs) and contributes to the malignant progression of GC, but mechanism(s) underlying aberrant STAT3 remain largely unknown. Here we demonstrated that the gene associated with retinoid interferon-induced mortality 19 (GRIM-19) was severely depressed or lost in GC and chronic atrophic gastritis (CAG) tissues and its loss contributed to GC tumorigenesis partly by activating STAT3 signaling. In primary human GC tissues, GRIM-19 was frequently depressed or lost and this loss correlated with advanced clinical stage, lymph node metastasis, H. pylori infection and poor overall survival of GC patients. In CAG tissues, GRIM-19 was progressively decreased along with its malignant transformation. Functionally, we indentified an oncogenic role of GRIM-19 loss in promoting GC tumorigenesis. Ectopic GRIM-19 expression suppressed GC tumor formation in vitro and in vivo by inducing cell cycle arrest and apoptosis. Moreover, we revealed that GRIM-19 inhibited STAT3 transcriptional activation and its downstream targets by reducing STAT3 nuclear distribution. Conversely, knockdown of GRIM-19 induced aberrant STAT3 activation and accelerated GC cell growth in vitro and in vivo, and this could be partly attenuated by the blockage of STAT3 activation. In addition, we observed subcellular redistributions of GRIM-19 characterized by peri-nuclear aggregates, non-mitochondria cytoplasmic distribution and nuclear invasion, which should be responsible for reduced STAT3 nuclear distribution. Our studies suggest that mitochondrial GRIM-19 could not only serve as an valuable prognostic biomarker for GC development, but also as a potential therapeutic target for STAT3-dependent carcinogenesis of GC.
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