title: Human microRNA-27a* targets Prf1 and GzmB expression to regulate NK-cell cytotoxicity.
abstract: Perforin (Prf1) and granzyme B (GzmB) are essential effector molecules for natural killer (NK)-cell cytotoxicity, but how Prf1 and GzmB expression is regulated during arming of NK cells is poorly defined. We show that human microRNA (miR)-27a* is a negative regulator of NK-cell cytotoxicity by silencing Prf1 and GzmB expression. Human miR-27a* specifically bound to the 3' untranslated regions of Prf1 and GzmB, down-regulating expression in both resting and activated NK cells, and it functioned as a fine-tuner for homeostasis of the net amount of the effector proteins. Consistent with miR-27a* having an inhibitory role, knockdown of miR-27a* in NK cells dramatically increased cytotoxicity in vitro and decreased tumor growth in a human tumor xenograft model. Thus, NK-cell cytotoxicity is regulated, in part, by microRNA, and modulating endogenous miR-27a* levels in NK cells represents a potential immunotherapeutic strategy.
authors.affiliation: Cell Therapy Research Center, Korea Research Institute of Bioscience and Biotechnology, 125 Gwahak-ro, Yuseong, Daejeon, Republic of Korea.
authors.forename: Tae-Don
authors.initials: TD
authors.lastname: Kim
authors.forename: Su Ui
authors.initials: SU
authors.lastname: Lee
authors.forename: Sohyun
authors.initials: S
authors.lastname: Yun
authors.forename: Hu-Nan
authors.initials: HN
authors.lastname: Sun
authors.forename: Suk Hyung
authors.initials: SH
authors.lastname: Lee
authors.forename: Jae Wha
authors.initials: JW
authors.lastname: Kim
authors.forename: Hwan Mook
authors.initials: HM
authors.lastname: Kim
authors.forename: Song-Kyu
authors.initials: SK
authors.lastname: Park
authors.forename: Chang Woo
authors.initials: CW
authors.lastname: Lee
authors.forename: Suk Ran
authors.initials: SR
authors.lastname: Yoon
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
authors.forename: Inpyo
authors.initials: I
authors.lastname: Choi
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000276:immunology* / Q000628:therapy; D005260:Female; D005312:Fetal Blood / Q000166:cytology; D020868:Gene Silencing; D015316:Genetic Therapy / Q000379:methods; D053804:Granzymes / Q000235:genetics*; D006801:Humans; D007694:Killer Cells, Natural / Q000166:cytology / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D035683:MicroRNAs / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C531388:MIRN27 microRNA, human; D035683:MicroRNAs; C510468:PRF1 protein, human; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes