title: Hydroquinone-induced miR-122 down-regulation elicits ADAM17 up-regulation, leading to increased soluble TNF-α production in human leukemia cells with expressed Bcr/Abl.
abstract: Studies on HQ-treated human leukemia K562 (Bcr/Abl-positive) cells were conducted to address the hydroquinone (HQ) mechanism that promotes soluble TNF-α (sTNF-α) production. HQ post-translationally down-regulated cell surface TNF-α expression increases the release of sTNF-α into K562 cell culture medium. Meanwhile, HQ increased ADAM17 mRNA stability, leading to ADAM17 up-regulation in HQ-treated cells. Knock-down of ADAM17 abrogated HQ-induced sTNF-α secretion. HQ-evoked miR-122 down-regulation was proven to promote ADAM17 mRNA stability and up-regulate ADAM17 expression. HQ-induced p38 MAPK and JNK activation were responsible for suppression of miR-122 promoter luciferase activity and miR-122 expression. Activation of p38 MAPK and JNK elicited phosphorylation of c-Jun, ATF-2 and c-Fos, and knock-down of c-Jun, ATF-2 and c-Fos restored miR-122 expression in HQ-treated cells. Chromatin immunoprecipitating and DNA affinity purification assay revealed c-Jun, ATF-2 and c-Fos binding to the miR-122 gene promoter region. Moreover, HQ-induced sTNF-α production in Bcr/Abl-positive leukemia cell lines KU812 and MEG-01 was also connected with miR-122 down-regulation and ADAM17 up-regulation, while HQ was unable to affect miR-122 and ADAM-17 expression on Bcr/Abl-negative leukemia U937 cells. Taken together, our data indicate that HQ induces down-regulation of miR-122 expression, leading to ADAM17 up-regulation and ADAM17-mediated TNF-α shedding. Consequently, HQ treatment increases the production of sTNF-α in leukemia cells with expressed Bcr/Abl.
authors.affiliation: Institute of Biomedical Sciences, National Sun Yat-Sen University, Kaohsiung 804, Taiwan.
authors.forename: Ying-Jung
authors.initials: YJ
authors.lastname: Chen
authors.forename: Long-Sen
authors.initials: LS
authors.lastname: Chang
mesh_terms: D051722:ADAM Proteins / Q000235:genetics / Q000378:metabolism*; D000072198:ADAM17 Protein; D001483:Base Sequence; D045744:Cell Line, Tumor; D017931:DNA Primers; D015536:Down-Regulation / Q000187:drug effects; D004789:Enzyme Activation; D016044:Fusion Proteins, bcr-abl / Q000378:metabolism*; D006801:Humans; D006873:Hydroquinones / Q000494:pharmacology*; D020014:K562 Cells; D007938:Leukemia / Q000378:metabolism*; D035683:MicroRNAs / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis*; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D017931:DNA Primers; D006873:Hydroquinones; C531907:MIRN122 microRNA, human; D035683:MicroRNAs; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016044:Fusion Proteins, bcr-abl; D051722:ADAM Proteins; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human; C031927:hydroquinone
keywords: ADAM17; AP-1; Hydroquinone; JNK; TNF-α; miR-122; p38 MAPK