title: Mitochondrial GRIM-19 as a potential therapeutic target for STAT3-dependent carcinogenesis of gastric cancer.
abstract: 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.
authors.affiliation: Chongqing 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.
authors.forename: Yi
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Neurosurgery, Xinqiao Hospital of Third Military Medical University, Chongqing 400038, PR China.
authors.forename: Meihua
authors.initials: M
authors.lastname: Yang
authors.affiliation: Department of Gastroenterology, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China.
authors.forename: Huajian
authors.initials: H
authors.lastname: Hu
authors.affiliation: Chongqing 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.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhao
authors.affiliation: Chongqing 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.|Department of Pathology, Dartmouth-Hitchcock Medical Center, Geisel School of Medicine at Dartmouth College, Lebanon, NH 03756, USA.
authors.forename: Liming
authors.initials: L
authors.lastname: Bao
authors.affiliation: Chongqing 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.|Animal Care Center, Children's Hospital of Chongqing Medical University, Chongqing 400014, PR China.
authors.forename: Daochao
authors.initials: D
authors.lastname: Huang
authors.affiliation: Chongqing 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.|Department of Gastroenterology, 416 Hospital of Nuclear Industry, Chengdu 610051, PR China.
authors.forename: Lihua
authors.initials: L
authors.lastname: Song
authors.affiliation: Chongqing 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.
authors.forename: Yang
authors.initials: Y
authors.lastname: Li
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism / Q000502:physiology*; D063646:Carcinogenesis / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D008875:Middle Aged; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D058990:Molecular Targeted Therapy; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism / Q000502:physiology*; D011379:Prognosis; D050796:STAT3 Transcription Factor / Q000235:genetics*; D013274:Stomach Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality / Q000473:pathology
chemical_list: D051017:Apoptosis Regulatory Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human
keywords: GRIM-19; STAT3; chronic atrophic gastritis; clinical outcome; gastric cancer