title: MicroRNA let-7a down-regulates MYC and reverts MYC-induced growth in Burkitt lymphoma cells.
abstract: Regulation of the MYC oncogene remains unclear. Using 10058-F4, a compound that inhibits MYC-MAX transcription factor, MYC protein and gene expression were down-regulated in Namalwa cells, a Burkitt lymphoma. Compound 10058-F4 decreased MYC mRNA (45%), MYC protein (50%), and cell growth (32%). MYC-MAX transcription factor was disrupted 24 h after treatment, resulting in transcriptional inhibition of target genes. Because microRNAs (miRNA) disrupt mRNA translation, let-7a, let-7b, and mir-98 were selected using bioinformatics for targeting MYC. Inhibition of MYC-MAX transcription factor with 10058-F4 increased levels of members of the let-7 family. In inhibited cells at 24 h, let-7a, let-7b, and mir-98 were induced 4.9-, 1.3-, and 2.4-fold, respectively, whereas mir-17-5p decreased 0.23-fold. These results were duplicated using microRNA multianalyte suspension array technology. Regulation of MYC mRNA by let-7a was confirmed by transfections with pre-let-7a. Overexpression of let-7a (190%) decreased Myc mRNA (70%) and protein (75%). Down-regulation of Myc protein and mRNA using siRNA MYC also elevated let-7a miRNA and decreased Myc gene expression. Inverse coordinate regulation of let-7a and mir-17-5p versus Myc mRNA by 10058-F4, pre-let-7a, or siRNA MYC suggested that both miRNAs are Myc-regulated. This supports previous results in lung and colon cancer where decreased levels of the let-7 family resulted in increased tumorigenicity. Here, pre-let-7a transfections led to down-regulation of expression of MYC and its target genes and antiproliferation in lymphoma cells. These findings with let-7a add to the complexity of MYC regulation and suggest that dysregulation of these miRNAs participates in the genesis and maintenance of the lymphoma phenotype in Burkitt lymphoma cells and other MYC-dysregulated cancers.
authors.affiliation: Department of Molecular Genetics, Cellular and Tissue Transplantation, Alfred I. duPont Hospital for Children, Wilmington, Delaware 19803, and Center for Applied Genomics, Public Health Research Institute, UMDNJ-New Jersey Medical School, Newark, USA.
authors.forename: Valerie B
authors.initials: VB
authors.lastname: Sampson
authors.forename: Nancy H
authors.initials: NH
authors.lastname: Rong
authors.forename: Jian
authors.initials: J
authors.lastname: Han
authors.forename: Qunying
authors.initials: Q
authors.lastname: Yang
authors.forename: Virginie
authors.initials: V
authors.lastname: Aris
authors.forename: Patricia
authors.initials: P
authors.lastname: Soteropoulos
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Petrelli
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Dunn
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Krueger
mesh_terms: D000818:Animals; D050976:Basic-Leucine Zipper Transcription Factors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics; D002051:Burkitt Lymphoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology*; D048708:Cell Growth Processes / Q000235:genetics; D015536:Down-Regulation; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D016259:Genes, myc; D006801:Humans; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D016271:Proto-Oncogene Proteins c-myc / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D051381:Rats
chemical_list: D050976:Basic-Leucine Zipper Transcription Factors; D035683:MicroRNAs; C067850:Myc associated factor X; D016271:Proto-Oncogene Proteins c-myc; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C487931:mirnlet7 microRNA, human