title: STAT1: A Novel Target of miR-150 and miR-223 Is Involved in the Proliferation of HTLV-I-Transformed and ATL Cells.
abstract: We have previously reported on the deregulation of cellular microRNAs involved in hematopoiesis and inflammation in human T-cell lymphotropic virus type 1 (HTLV-I)-transformed cells. In this study, we demonstrate that miR-150 and miR-223 specifically target the signal transducer and activator of transcription 1 (STAT1) 3' untranslated region, reducing STAT1 expression and dampening STAT1-dependent signaling in human T cells. The effects of miR-150 and miR-223 on endogenous STAT1 were confirmed using inducible cell lines. Our studies also showed that miR-150 expression is upregulated by interleukin-2 signaling in adult T cell leukemia/lymphoma (ATL) cells. HTLV-I-transformed and ATL-derived cells have reduced levels of miR150 and miR223 expression, which coincide with increased STAT1 expression and STAT1-dependent signaling. Knockdown of STAT1 by short hairpin RNA demonstrated that the constitutive activation of STAT1 is required for the continuous proliferation of HTLV-I-transformed cells. Our studies further demonstrate that increased expression of STAT1 in ATL cells is associated with higher levels of major histocompatibility complex class I expression. Previous studies have demonstrated that the pressure exerted by natural killer (NK) cells in vivo can edit leukemic tumor cells by forcing an increased expression of major histocompatibility complex class I to escape immune clearance. STAT1-expressing tumor cells produce more aggressive tumors because they cannot be eliminated by NK cells. Our results suggest that therapeutic approaches using combined targeting of STAT1 and MHC class I may be an effective approach to activate NK cell-mediated clearance of ATL tumor cells.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Ramona
authors.initials: R
authors.lastname: Moles
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA.
authors.forename: Marcia
authors.initials: M
authors.lastname: Bellon
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS, USA. Electronic address: cnicot@kumc.edu.
authors.forename: Christophe
authors.initials: C
authors.lastname: Nicot
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics / Q000276:immunology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002472:Cell Transformation, Viral / Q000235:genetics; D015973:Gene Expression Regulation, Leukemic / Q000235:genetics*; D015395:Histocompatibility Antigens Class I / Q000276:immunology; D015368:Human T-lymphotropic virus 1; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D035683:MicroRNAs / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050794:STAT1 Transcription Factor / Q000235:genetics*; D014162:Transfection
chemical_list: D020413:3' Untranslated Regions; D015395:Histocompatibility Antigens Class I; D035683:MicroRNAs; D050794:STAT1 Transcription Factor; C533097:MIR150, human; C525067:MIR223, human; C494079:STAT1 protein, human