title: Diagnostic and prognostic impact of serum-soluble UL16-binding protein 2 in lung cancer patients.
abstract: UL16-binding protein 2 (ULBP2) is one of the ligands for NKG2D (NKG2DL). ULBP2 expression is induced in transformed cells and is recognized by immune effector cells via the activating NKG2D immunoreceptor. Soluble forms of NKG2DL have been reported in the serum of patients with several types of cancer. The present study investigated the diagnostic and prognostic significance of serum-soluble ULBP2 (sULBP2) in lung cancer patients. We used flow cytometry to evaluate the surface expression of NKG2DL by various lung cancer cells, while sULBP2 was measured using our original ELISA. In addition, the immunological effect of sULBP2 on peripheral blood mononuclear cells (PBMC) was examined by the (51) Cr release assay. We found that ULBP2 was highly expressed and that the sULBP2 level was elevated in supernatants of cultured non-small-cell lung cancer (NSCLC) cells as well as in the serum of NSCLC patients. ULBP2 levels were especially high in squamous cell carcinoma (SQ) patients. Clinical stage IIIB and IV NSCLC patients with a sULBP2 level ≥ 8.7 pg/mL showed significantly shorter survival than patients with sULBP2 <8.7 pg/mL. In multivariate analysis, a sULBP2 level ≥ 8.7 pg/mL (hazard ratio [HR], 2.13; P = 0.038) and clinical stage IV (HR, 2.65; P = 0.019) were independent determinants of a poor outcome. As a possible mechanism, we demonstrated that sULBP2 directly suppresses the cytolytic activity of PBMC. In conclusion, ULBP2 is the most significant NKG2DL for lung cancer, and sULBP2 is useful in the diagnosis of SQ and as a prognostic indicator for patients with advanced NSCLC.
authors.affiliation: Division of Medical Oncology and Molecular Respirology, Department of Multidisciplinary Internal Medicine, Faculty of Medicine, Tottori University, Tottori-ken, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Yamaguchi
authors.forename: Hiroki
authors.initials: H
authors.lastname: Chikumi
authors.forename: Asuka
authors.initials: A
authors.lastname: Shimizu
authors.forename: Miyako
authors.initials: M
authors.lastname: Takata
authors.forename: Naoki
authors.initials: N
authors.lastname: Kinoshita
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Hashimoto
authors.forename: Masaki
authors.initials: M
authors.lastname: Nakamoto
authors.forename: Shinji
authors.initials: S
authors.lastname: Matsunaga
authors.forename: Jun
authors.initials: J
authors.lastname: Kurai
authors.forename: Naomi
authors.initials: N
authors.lastname: Miyake
authors.forename: Shingo
authors.initials: S
authors.lastname: Matsumoto
authors.forename: Masanari
authors.initials: M
authors.lastname: Watanabe
authors.forename: Akira
authors.initials: A
authors.lastname: Yamasaki
authors.forename: Tadashi
authors.initials: T
authors.lastname: Igishi
authors.forename: Naoto
authors.initials: N
authors.lastname: Burioka
authors.forename: Eiji
authors.initials: E
authors.lastname: Shimizu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000097:blood / Q000175:diagnosis*; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry; D058851:GPI-Linked Proteins / Q000097:blood; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000097:blood*; D008175:Lung Neoplasms / Q000097:blood / Q000175:diagnosis*; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000378:metabolism*; D011379:Prognosis; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D058851:GPI-Linked Proteins; D047908:Intracellular Signaling Peptides and Proteins; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; C423231:ULBP1 protein, human