title: Overexpression of natural killer group 2 member D ligands predicts favorable prognosis in cholangiocarcinoma.
abstract: The natural killer group 2 member D (NKG2D) receptor and its ligands are important mediators of immune responses to tumors. NKG2D ligands are overexpressed in several malignant tumor types; however, the prognostic value of these ligands is unclear. Here, we aimed to elucidate the role of NKG2D ligands in extrahepatic cholangiocarcinoma (EHCC). We therefore investigated the expression of the NKG2D receptor and its ligands MHC class I chain-related proteins A and B (MICA/B), unique long 16 binding protein (ULBP) 1, and ULBP2/5/6 in resected specimens from 82 patients with EHCC. All NKG2D ligands were highly expressed in EHCC. High expression of MICA/B or ULBP2/5/6 correlated with overall and disease-free survival. In contrast, high expression of ULBP1 was significantly associated with improved overall survival, but not disease-free survival. Concurrent high expression of multiple NKG2D ligands revealed significantly better overall and disease-free survival than that observed with the overexpression of any one NKG2D ligand. Co-expression of multiple NKG2D ligands was an independent prognostic indicator of improved survival. Furthermore, co-overexpression of multiple NKG2D ligands was significantly correlated with high expression of the NKG2D receptor. Inhibiting interactions between multiple NKG2D ligands and the NKG2D receptor might be a promising approach for controlling cancer progression and improving patient prognosis in EHCC.
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Tsukagoshi
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.|Department of Cancer Immunotherapy, Kanagawa Cancer Center, Yokohama, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Wada
authors.affiliation: Department of Molecular Pharmacology and Oncology, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokobori
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Bolag
authors.initials: B
authors.lastname: Altan
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Norihiro
authors.initials: N
authors.lastname: Ishii
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Akira
authors.initials: A
authors.lastname: Watanabe
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Kubo
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Fumiyoshi
authors.initials: F
authors.lastname: Saito
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Araki
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hideki
authors.initials: H
authors.lastname: Suzuki
authors.affiliation: Department of Surgery and Laparoscopic Surgery, Gunma Prefecture Saiseikai-Maebashi Hospital, Maebashi, Japan.
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Hosouchi
authors.affiliation: Department of General Surgical Science, Gunma University Graduate School of Medicine, Maebashi, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kuwano
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001650:Bile Duct Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D001653:Bile Ducts, Intrahepatic / Q000473:pathology; D014408:Biomarkers, Tumor / Q000032:analysis*; D018281:Cholangiocarcinoma / Q000378:metabolism* / Q000401:mortality; D005260:Female; D058851:GPI-Linked Proteins / Q000096:biosynthesis; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis; D006801:Humans; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis; D053208:Kaplan-Meier Estimate; D008024:Ligands; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D011379:Prognosis; D016016:Proportional Hazards Models; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D008024:Ligands; C099187:MHC class I-related chain A; C098080:MICB antigen; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human
keywords: Cholangiocarcinoma; MHC class I chain-related proteins A and B; immunohistochemistry; natural killer group 2 member D; unique long 16 binding protein