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  • 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.
    Author: Chen YJ, Chang LS.
    Journal: Biochem Pharmacol; 2013 Sep 01; 86(5):620-31. PubMed ID: 23791922.
    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.
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