Regulation of p53-targeting microRNAs by polycyclic aromatic hydrocarbons: Implications in the etiology of multiple myeloma

Michael W. Gordon, Fang Yan, Xiaoming Zhong, Pranab Behari Mazumder, Zijun Y. Xu-Monette, Dehui Zou, Ken H. Young, Kenneth S. Ramos, Yong Li

Research output: Contribution to journalArticle

36 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1060-1069
Number of pages10
JournalMolecular Carcinogenesis
Volume54
Issue number10
DOIs
StatePublished - Oct 1 2015
Externally publishedYes

Keywords

  • MicroRNAs
  • Multiple myeloma
  • P53
  • Polycyclic aromatic hydrocarbons
  • Toxicants

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

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  • Cite this

    Gordon, M. W., Yan, F., Zhong, X., Mazumder, P. B., Xu-Monette, Z. Y., Zou, D., Young, K. H., Ramos, K. S., & Li, Y. (2015). Regulation of p53-targeting microRNAs by polycyclic aromatic hydrocarbons: Implications in the etiology of multiple myeloma. Molecular Carcinogenesis, 54(10), 1060-1069. https://doi.org/10.1002/mc.22175