title: Induction of miR-21-PDCD4 signaling by tungsten carbide-cobalt nanoparticles in JB6 cells involves ROS-mediated MAPK pathways.
abstract: Tungsten carbide-cobalt (WC-Co) nanoparticle composites have wide applications because of their hardness and toughness. WC-Co was classified as "probably carcinogenic" to humans by the International Agency for Research on Cancer (IARC) in 2003. It is believed that the toxicity and carcinogenesis of WC-Co is associated with particle size. Recent studies demonstrated that the tumor suppressor gene programmed cell death 4 (PDCD4) and its upstream regulator miR-21 have been considered as oncogenes for novel cancer prevention or anticancer therapies. The present study examined the effects of WC-Co nanoparticles on miR-21-PDCD4 signaling in a mouse epidermal cell line (JB6 P+). The results showed that (i) exposure of JB6 cells to WC-Co stimulated a increase of miR-21 generation; (ii) WC-Co also caused inhibition of PDCD4, a tumor suppressor protein and downstream target of miR-21, expression in JB6 cells; (iii) inhibition of ERKs with ERK inhibitor U0126 significantly reversed WC-Cominus;induced PDCD4 inhibition, but inhibition of p38 with p38 inhibitor SB203580 did not; and (iv) ROS scavengers, N-acetyl-L-cysteine and catalase, blocked the inhibitory effect of WC-Co on PDCD4 expression, while superoxide dismutase promoted the inhibitory effect. These findings demonstrate that WC-Co nanoparticles induce miR-21 generation, but inhibit PDCD4 production, which may be mediated through ROS, especially endogenous H2O2, and ERK pathways. Unraveling the complex mechanisms associated with these events may provide insights into the initiation and progression of WC-Co-induced carcinogenesis.
authors.affiliation: Graduate Center for Toxicology, College of Medicine, University of Kentucky, Lexington, KY 40503, USA.
authors.forename: Lichao
authors.initials: L
authors.lastname: Hou
authors.forename: Linda
authors.initials: L
authors.lastname: Bowman
authors.forename: Terence G
authors.initials: TG
authors.lastname: Meighan
authors.forename: Xianglin
authors.initials: X
authors.lastname: Shi
authors.forename: Min
authors.initials: M
authors.lastname: Ding
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D003035:Cobalt / Q000009:adverse effects / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006861:Hydrogen Peroxide / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism*; D053758:Nanoparticles; D009570:Nitriles / Q000494:pharmacology; D016273:Occupational Exposure; D011725:Pyridines / Q000494:pharmacology; D016601:RNA-Binding Proteins / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects* / Q000502:physiology; D017973:Tungsten Compounds / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D009570:Nitriles; C498443:Pdcd4 protein, mouse; D011725:Pyridines; D016601:RNA-Binding Proteins; D017382:Reactive Oxygen Species; D017973:Tungsten Compounds; C113580:U 0126; C002802:tungsten carbide; D003035:Cobalt; D006861:Hydrogen Peroxide; D020929:Mitogen-Activated Protein Kinase Kinases; C093642:SB 203580