title: Signal transducer and activator of transcription-3 induces microRNA-155 expression in chronic lymphocytic leukemia.
abstract: MicroRNA (miR) abnormalities play a key role in the pathogenesis of chronic lymphocytic leukemia (CLL). High levels of miR-155 have been detected in human neoplasms, and overexpression of miR-155 has been found to induce lymphoma in mice. High levels of miR-155 were detected in CLL cells and STAT3, which is known to induce miR-21 and miR-181b-1 expression, is constitutively activated in CLL. Given these findings, we hypothesized that STAT3 induces miR-155. Sequence analysis revealed that the miR-155 promoter harbors two putative STAT3 binding sites. Therefore, truncated miR-155 promoter constructs and STAT3 small interfering RNA (siRNA) were co-transfected into MM1 cells. Of the two putative binding sites, STAT3-siRNA reduced the luciferase activity of the construct containing the 700-709 bp STAT3 binding site, suggesting that this site is involved in STAT3-induced transcription. Electrophoretic mobility shift assay confirmed that STAT3 bound to the miR-155 promoter in CLL cells, and chromatin immunoprecipitation and luciferase assay confirmed that STAT3 bound to the 700-709 bp but not the 615-624 bp putative STAT3 binding site in CLL cells. Finally, STAT3-small hairpin RNA downregulated miR-155 gene expression, suggesting that constitutively activated STAT3 binds to the miR-155 gene promoter. Together, these results suggest that STAT3 activates miR-155 in CLL cells.
authors.affiliation: Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Srdana
authors.initials: S
authors.lastname: Grgurevic
authors.forename: Zhiming
authors.initials: Z
authors.lastname: Liu
authors.forename: David
authors.initials: D
authors.lastname: Harris
authors.forename: Uri
authors.initials: U
authors.lastname: Rozovski
authors.forename: George A
authors.initials: GA
authors.lastname: Calin
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Keating
authors.forename: Zeev
authors.initials: Z
authors.lastname: Estrov
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D006801:Humans; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic / Q000235:genetics; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation; D014162:Transfection
chemical_list: C524942:MIRN155 microRNA, human; D035683:MicroRNAs; D050796:STAT3 Transcription Factor