title: The modulation of Dicer regulates tumor immunogenicity in melanoma.
abstract: MicroRNAs (miRs) are small non-coding RNAs that regulate most cellular protein networks by targeting mRNAs for translational inhibition or degradation. Dicer, a type III endoribonuclease, is a critical component in microRNA biogenesis and is required for mature microRNA production. Abnormal Dicer expression occurs in numerous cancer types and correlates with poor patient prognosis. For example, increased Dicer expression in melanoma is associated with more aggressive tumors (higher tumor mitotic index and depth of invasion) and poor patient prognosis. However, the role that Dicer plays in melanoma development and immune evasion remains unclear. Here, we report on a newly discovered relationship between Dicer expression and tumor immunogenicity. To investigate Dicer's role in regulating melanoma immunogenicity, Dicer knockdown studies were performed. We found that B16F0-Dicer deficient cells exhibited decreased tumor growth compared to control cells and were capable of inducing anti-tumor immunity. The decrease in tumor growth was abrogated in immunodeficient NSG mice and was shown to be dependent upon CD8+ T cells. Dicer knockdown also induced a more responsive immune gene profile in melanoma cells. Further studies demonstrated that CD8+ T cells preferentially killed Dicer knockdown tumor cells compared to control cells. Taken together, we present evidence which links Dicer expression to tumor immunogenicity in melanoma.
authors.affiliation: Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.
authors.forename: Nicholas C
authors.initials: NC
authors.lastname: Hoffend
authors.affiliation: Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.|Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, USA.
authors.forename: William J
authors.initials: WJ
authors.lastname: Magner
authors.affiliation: Laboratory of Molecular Medicine, Department of Immunology, Roswell Park Cancer Institute, Buffalo, New York, USA.|Department of Medicine, State University of New York, Buffalo, New York, USA.|Department of Microbiology and Immunology, School of Medicine and Biomedical Sciences, State University of New York, Buffalo, New York, USA.
authors.forename: Thomas B
authors.initials: TB
authors.lastname: Tomasi
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000473:pathology; D045744:Cell Line, Tumor; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000276:immunology*; D005260:Female; D008297:Male; D008546:Melanoma, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology; D011379:Prognosis; D043244:Ribonuclease III / Q000235:genetics / Q000276:immunology*
chemical_list: D035683:MicroRNAs; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases
keywords: CD8+ T cells; Dicer; immunogenicity; melanoma; microRNA