title: Silencing NKG2D ligand-targeting miRNAs enhances natural killer cell-mediated cytotoxicity in breast cancer.
abstract: NKG2D is one of the major activating receptors of natural killer (NK) cells and binds to several ligands (NKG2DLs). NKG2DLs are expressed on malignant cells and sensitize them to early elimination by cytotoxic lymphocytes. We investigated the clinical importance of NKG2DLs and the mechanism of NKG2DL regulation in breast cancer (BC). Among the NKG2DLs MICA/B and ULBP1/2/3, the expression levels of MICA/B in BC tissues were inversely associated with the Tumor Node Metastasis stage. We first found that the high expression of MICB, but not MICA, was an independent prognostic factor for overall survival in patients with BC. Investigation into the mechanism revealed that a group of microRNAs (miRNAs) belonging to the miR-17-92 cluster, especially miR-20a, decreased the expression of ULBP2 and MICA/B. These miRNAs downregulated the expression of MICA/B by targeting the MICA/B 3'-untranslated region and downregulated ULBP2 by inhibiting the MAPK/ERK signaling pathway. Functional analysis showed that the silencing of NKG2DL-targeting miRNAs in BC cells increased NK cell-mediated cytotoxicity in vitro and inhibited immune escape in vivo. In addition, histone deacetylase inhibitors (HDACis) increased NKG2DL expression in BC cells by inhibiting members of the miR-17-92 cluster. Thus, targeting miRNAs with antisense inhibitors or HDACis may represent a novel approach for increasing the immunogenicity of BC.
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.
authors.forename: Jiaying
authors.initials: J
authors.lastname: Shen
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Pan
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Chengyong
authors.initials: C
authors.lastname: Du
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.
authors.forename: Wengong
authors.initials: W
authors.lastname: Si
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Minya
authors.initials: M
authors.lastname: Yao
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.|Clinical Research Center, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Liang
authors.initials: L
authors.lastname: Xu
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.
authors.forename: Huilin
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.
authors.forename: Mingjie
authors.initials: M
authors.lastname: Xu
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.
authors.forename: Danni
authors.initials: D
authors.lastname: Chen
authors.affiliation: Department of Biological Sciences, National University of Singapore, 117543, Singapore.
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.affiliation: Department of Breast Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou, 310003, China.
authors.forename: Peifen
authors.initials: P
authors.lastname: Fu
authors.affiliation: Program of Cancer Innovative Therapeutics, Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, College of Medicine, Zhejiang University, 79 Qingchun Road, Hangzhou 310000, China.|Department of Pathology and Laboratory Medicine, Medical University of South Carolina, Charleston, SC 29425, USA.
authors.forename: Weimin
authors.initials: W
authors.lastname: Fan
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006801:Humans; D007694:Killer Cells, Natural; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000235:genetics / Q000276:immunology*; D061986:MCF-7 Cells; D008297:Male; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000276:immunology*; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000235:genetics / Q000276:immunology*; D009363:Neoplasm Proteins / Q000235:genetics / Q000276:immunology; D012334:RNA, Neoplasm / Q000235:genetics / Q000276:immunology*
chemical_list: D056572:Histone Deacetylase Inhibitors; C527085:KLRK1 protein, human; C534451:MIRN20a microRNA, human; D035683:MicroRNAs; D055655:NK Cell Lectin-Like Receptor Subfamily K; D009363:Neoplasm Proteins; D012334:RNA, Neoplasm