title: Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1.
abstract: The RNase III endonuclease Dicer plays a key role in generation of microRNAs (miRs). We hypothesized that Dicer regulates cancer cell susceptibility to immune surveillance through miR processing. Indeed, Dicer disruption up-regulated intercellular cell adhesion molecule (ICAM)-1 and enhanced the susceptibility of tumor cells to antigen-specific lysis by cytotoxic T-lymphocytes (CTLs), while expression of other immunoregulatory proteins examined was not affected. Blockade of ICAM-1 inhibited the specific lysis of CTLs against Dicer-disrupted cells, indicating a pivotal role of ICAM-1 in the interaction between tumor cells and CTL. Both miR-222 and -339 are down-regulated in Dicer-disrupted cells and directly interacted with the 3' untranslated region (UTR) of ICAM-1 mRNA. Modulation of Dicer or these miRs inversely correlated with ICAM-1 protein expression and susceptibility of U87 glioma cells to CTL-mediated cytolysis while ICAM-1 mRNA levels remained stable. Immunohistochemical and in situ hybridization analyses of 30 primary glioblastoma tissues demonstrated that expression of Dicer, miR-222, or miR-339 was inversely associated with ICAM-1 expression. Taken together, Dicer is responsible for the generation of the mature miR-222 and -339, which suppress ICAM-1 expression on tumor cells, thereby down-regulating the susceptibility of tumor cells to CTL-mediated cytolysis. This study suggests development of novel miR-targeted therapy to promote cytolysis of tumor cells.
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
authors.forename: Ryo
authors.initials: R
authors.lastname: Ueda
authors.forename: Gary
authors.initials: G
authors.lastname: Kohanbash
authors.forename: Kotaro
authors.initials: K
authors.lastname: Sasaki
authors.forename: Mitsugu
authors.initials: M
authors.lastname: Fujita
authors.forename: Xinmei
authors.initials: X
authors.lastname: Zhu
authors.forename: Edward R
authors.initials: ER
authors.lastname: Kastenhuber
authors.forename: Heather A
authors.initials: HA
authors.lastname: McDonald
authors.forename: Douglas M
authors.initials: DM
authors.lastname: Potter
authors.forename: Ronald L
authors.initials: RL
authors.lastname: Hamilton
authors.forename: Michael T
authors.initials: MT
authors.lastname: Lotze
authors.forename: Saleem A
authors.initials: SA
authors.lastname: Khan
authors.forename: Robert W
authors.initials: RW
authors.lastname: Sobol
authors.forename: Hideho
authors.initials: H
authors.lastname: Okada
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D005434:Flow Cytometry; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045325:HCT116 Cells; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000378:metabolism*; D008156:Luciferases / Q000235:genetics / Q000378:metabolism; D035683:MicroRNAs / Q000235:genetics*; D009154:Mutation; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology / Q000276:immunology*; D014162:Transfection
chemical_list: D053487:DEAD-box RNA Helicases; D018799:Intercellular Adhesion Molecule-1; D008156:Luciferases; D035683:MicroRNAs; D012333:RNA, Messenger; D043244:Ribonuclease III; C525710:MIR222, human; C543820:MIRN339 microRNA, human; C408087:DICER1 protein, human