title: Glyoxalase I drives epithelial-to-mesenchymal transition via argpyrimidine-modified Hsp70, miR-21 and SMAD signalling in human bronchial cells BEAS-2B chronically exposed to crystalline silica Min-U-Sil 5: Transformation into a neoplastic-like phenotype.
abstract: Glyoxalase I (Glo1) is the main scavenging enzyme of methylglyoxal (MG), a potent precursor of advanced glycation end products (AGEs). AGEs are known to control multiple biological processes, including epithelial to mesenchymal transition (EMT), a multistep phenomenon associated with cell transformation, playing a major role in a variety of diseases, including cancer. Crystalline silica is a well-known occupational health hazard, responsible for a great number of human pulmonary diseases, such as silicosis. There is still much debate concerning the carcinogenic role of crystalline silica, mainly due to the lack of a causal demonstration between silica exposure and carcinogenesis. It has been suggested that EMT might play a role in crystalline silica-induced lung neoplastic transformation. The aim of this study was to investigate whether, and by means of which mechanism, the antiglycation defence Glo1 is involved in Min-U-Sil 5 (MS5) crystalline silica-induced EMT in BEAS-2B human bronchial epithelial cells chronically exposed, and whether this is associated with the beginning of a neoplastic-like transformation process. By using gene silencing/overexpression and scavenging/inhibitory agents, we demonstrated that MS5 induced hydrogen peroxide-mediated c-Jun-dependent Glo1 up-regulation which resulted in a decrease in the Argpyrimidine-modified Hsp70 protein level which triggered EMT in a novel mechanism involving miR-21 and SMAD signalling. The observed EMT was associated with a neoplastic-like phenotype. The results obtained provide a causal in vitro demonstration of the MS5 pro-carcinogenic transforming role and more importantly they provide new insights into the mechanisms involved in this process, thus opening new paths in research concerning the in vivo study of the carcinogenic potential of crystalline silica.
authors.affiliation: Department of Experimental Medicine, School of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy. Electronic address: cinzia.antognelli@unipg.it.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Antognelli
authors.affiliation: Department of Medicine, School of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy. Electronic address: angela.gambelunghe@unipg.it.
authors.forename: Angela
authors.initials: A
authors.lastname: Gambelunghe
authors.affiliation: Department of Medicine, School of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy. Electronic address: giacomo.muzi@unipg.it.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Muzi
authors.affiliation: Department of Experimental Medicine, School of Medicine and Surgery, University of Perugia, Piazzale L. Severi 1, 06129 Perugia, Italy. Electronic address: vincenzo.talesa@unipg.it.
authors.forename: Vincenzo Nicola
authors.initials: VN
authors.lastname: Talesa
mesh_terms: D001980:Bronchi / Q000187:drug effects / Q000473:pathology; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects / Q000235:genetics*; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis* / Q000737:chemistry / Q000235:genetics; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics; D007791:Lactoylglutathione Lyase / Q000235:genetics*; D035683:MicroRNAs / Q000235:genetics*; D009952:Ornithine / Q000031:analogs & derivatives / Q000737:chemistry; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D011743:Pyrimidines / Q000737:chemistry; D011765:Pyruvaldehyde / Q000008:administration & dosage; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D012822:Silicon Dioxide / Q000633:toxicity; D051785:Smad Proteins / Q000235:genetics*
chemical_list: D018840:HSP70 Heat-Shock Proteins; C524940:MIRN21 microRNA, human; D035683:MicroRNAs; D011743:Pyrimidines; D017382:Reactive Oxygen Species; D051785:Smad Proteins; C107313:argpyrimidine; D011765:Pyruvaldehyde; D012822:Silicon Dioxide; D009952:Ornithine; D048031:JNK Mitogen-Activated Protein Kinases; D007791:Lactoylglutathione Lyase
keywords: Argpyrimidine; EMT; Glyoxalase I; Hydrogen peroxide; Min-U-Sil 5; SMADs; miR-21