title: MicroRNA-9 plays a role in interleukin-10-mediated expression of E-cadherin in acute myelogenous leukemia cells.
abstract: We previously showed that the CD82/signal transducer and activator of transcription/interleukin-10 (IL-10) axis is activated in CD34+/CD38-AML cells that favor the bone marrow microenvironment. The present study explored the novel biological function of IL-10 in regulation of expression of adhesion molecules in AML cells and found that exposing AML cells to IL-10 induced expression of E-cadherin, but not other adhesion molecules, including VLA4, CD29, and LFA1. Downregulation of E-cadherin with an siRNA suppressed the adhesion of leukemia cells to bone marrow-derived mesenchymal stem cells and enhanced the anti-leukemia effect of cytarabine. A microRNA (miRNA) database search identified an miR-9 as a candidate miRNA binding onto the 3'-UTR of E-cadherin and regulating its expression. Notably, treatment of leukemia cells with IL-10 decreased miR-9 expression through hypermethylation of the miR-9 CpG islands. In addition, downregulation of DNA methyltransferase 3A by siRNAs decreased E-cadherin expression in parallel with an increase in levels of miR-9 in leukemia cells. Notably, short hairpin RNA-mediated IL-10 downregulation impaired engraftment of human AML cells and enhanced the anti-leukemia effect of cytarabine in conjunction with miR-9 upregulation and E-cadherin downregulation in a human AML xenograft model. Taken together, the IL-10/E-cadherin axis may be a promising therapeutic target for treating AML.
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.|Department of Immunology, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: Chie
authors.initials: C
authors.lastname: Nishioka
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.|Department of Hematology, Fukushima Medical University, Fukushima, Japan.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Ikezoe
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.|Department of Hematology, Fukushima Medical University, Fukushima, Japan.|Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.affiliation: Department of Hematology, The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.
authors.forename: Kailin
authors.initials: K
authors.lastname: Xu
authors.affiliation: Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Yokoyama
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000208:Acute Disease; D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D015820:Cadherins / Q000235:genetics* / Q000378:metabolism; D002448:Cell Adhesion / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D018899:CpG Islands / Q000235:genetics; D003561:Cytarabine / Q000494:pharmacology; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation / Q000187:drug effects; D000090205:DNA Methyltransferase 3A; D015973:Gene Expression Regulation, Leukemic / Q000187:drug effects*; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology*; D007951:Leukemia, Myeloid / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016019:Survival Analysis; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; D000964:Antimetabolites, Antineoplastic; D015820:Cadherins; C000717967:DNMT3A protein, human; C000715535:Dnmt3a protein, mouse; C541874:MIRN92 microRNA, human; D035683:MicroRNAs; D003561:Cytarabine; D016753:Interleukin-10; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A
keywords: 
  AML
  ; DNMT3A; E-cadherin; IL-10; miR-9