Dicer-regulated microRNAs 222 and 339 promote resistance of cancer cells to cytotoxic T-lymphocytes by down-regulation of ICAM-1.
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.
Ueda
Ryo
R
Department of Neurological Surgery, University of Pittsburgh School of Medicine, Pittsburgh, PA 15213, USA.
Kohanbash
Gary
G
Sasaki
Kotaro
K
Fujita
Mitsugu
M
Zhu
Xinmei
X
Kastenhuber
Edward R
ER
McDonald
Heather A
HA
Potter
Douglas M
DM
Hamilton
Ronald L
RL
Lotze
Michael T
MT
Khan
Saleem A
SA
Sobol
Robert W
RW
Okada
Hideho
H
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
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