title: Regulation of p53-targeting microRNAs by polycyclic aromatic hydrocarbons: Implications in the etiology of multiple myeloma.
abstract: Multiple myeloma (MM) is a common and deadly cancer of blood plasma cells. A unique feature of MM is the extremely low somatic mutation rate of the p53 tumor suppressor gene, in sharp contrast with about half of all human cancers where this gene is frequently mutated. Eleven miRNAs have been reported to repress p53 through direct interaction with the 3' untranslated region. The expression of nine of them is higher in MM plasma cells than in healthy donor counterparts, suggesting that miRNA overexpression is responsible for p53 inactivation in MM. Here, we report that the environmental carcinogen benzo[a]pyrene (BaP) upregulated the expression of seven p53-targeting miRNAs (miR-25, miR-15a, miR-16, miR-92, miR-125b, miR-141, and miR-200a), while 2,3,7,8-tetrachlorodibenzo-ρ-dioxin (TCDD) upregulated two of them (miR-25 and miR-92) in MM cells. The miR-25 promoter was activated by both BaP and TCDD, and this response was mediated by the aryl hydrocarbon receptor (AhR). We screened 727 compounds that inhibit MM cell survival and down-regulate the expression of p53-targeting miRNAs. We found that (-)-epigallocatechin-3-gallate (EGCG), a constituent of green tea and a major component of the botanical drug Polyphenon® E, reduced the expression of four p53-targeting miRNAs, including miR-25, miR-92, miR-141, and miR-200a. Collectively, these data implicate polycyclic aromatic hydrocarbons and AhR in the regulation of p53-targeting miRNAs in MM and identify a potential therapeutic and preventive agent to combat this deadly disease.
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Michael W
authors.initials: MW
authors.lastname: Gordon
authors.affiliation: Department of Histology and Embryology, Southern Medical University, Guangzhou, Guangdong, China.
authors.forename: Fang
authors.initials: F
authors.lastname: Yan
authors.affiliation: Department of Cardiology, Huaihe Hospital of Henan University, Kaifeng, Henan, China.
authors.forename: Xiaoming
authors.initials: X
authors.lastname: Zhong
authors.affiliation: Department of Biotechnology, Assam University, Silchar, Assam, India.
authors.forename: Pranab Behari
authors.initials: PB
authors.lastname: Mazumder
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Zijun Y
authors.initials: ZY
authors.lastname: Xu-Monette
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Dehui
authors.initials: D
authors.lastname: Zou
authors.affiliation: Department of Hematopathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
authors.forename: Ken H
authors.initials: KH
authors.lastname: Young
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Kenneth S
authors.initials: KS
authors.lastname: Ramos
authors.affiliation: Department of Biochemistry and Molecular Biology, School of Medicine, University of Louisville, Louisville, Kentucky.
authors.forename: Yong
authors.initials: Y
authors.lastname: Li
mesh_terms: D020413:3' Untranslated Regions / Q000187:drug effects / Q000235:genetics; D001564:Benzo(a)pyrene / Q000009:adverse effects; D002274:Carcinogens, Environmental / Q000009:adverse effects; D002392:Catechin / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000235:genetics*; D011084:Polycyclic Aromatic Hydrocarbons / Q000494:pharmacology*; D011401:Promoter Regions, Genetic / Q000187:drug effects / Q000235:genetics; D018336:Receptors, Aryl Hydrocarbon / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D015854:Up-Regulation / Q000187:drug effects / Q000235:genetics
chemical_list: D020413:3' Untranslated Regions; D002274:Carcinogens, Environmental; D035683:MicroRNAs; D011084:Polycyclic Aromatic Hydrocarbons; D018336:Receptors, Aryl Hydrocarbon; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D001564:Benzo(a)pyrene; D002392:Catechin; C045651:epigallocatechin gallate
keywords: microRNAs; multiple myeloma; p53; polycyclic aromatic hydrocarbons; toxicants