title: MICA/B and ULBP1 NKG2D ligands are independent predictors of good prognosis in cervical cancer.
abstract: BACKGROUND
  NKG2D (natural killer group 2, member D) is thought to play an important role in mediating the activation of anticancer immune response. Expression of NKG2D ligands (NKG2DLs) is pronounced in malignancies and the heterogeneity of NKG2DL expression remains unclear. Here, we investigate the expression and clinical significance of NKG2DLs in cervical cancer.
  
  
  METHODS
  Immunohistochemical analyses of MICA/B, ULBP1, ULBP2, ULBP3, RAET1E, and RAET1G were performed using tissue microarray analysis of 200 cervical cancers, 327 high-grade cervical intraepithelial neoplasias (CINs), 99 low-grade CINs, and 541 matched nonadjacent normal cervical epithelial tissues and compared the data with clinicopathologic variables, including the survival of cervical cancer patients.
  
  
  RESULTS
  MICA/B, ULBP1, and RAET1E expression was higher in cervical cancer than in low-grade CIN (p<0.001, p=0.012, p=0.013, respectively) and normal cervix (all p<0.001). Among these markers, expression of ULBP1 was significantly different depending on patient tumor stage (p=0.010) and tumor size (p=0.045). ULBP1 expression was correlated with MICA/B (p<0.001) and ULBP2 (p=0.002) expression in cervical cancer. While MICA/B+ or ULBP1+ patients had improved disease-free survival time (p=0.027 and p=0.009, respectively) relative to that of the low expression group, RAET1E+ or RAET1G+ was correlated with shorter survival time (p=0.018 and p=0.029, respectively). However, in terms of overall survival, the ULBP1+ group had significantly longer survival time than the low expression group (p=0.009). Multivariate analysis indicated that MICA/B+/ULBP1+ (HR=0.16, p=0.015) and ULBP1+ (HR=0.31, p=0.024) are independent prognostic factors of disease-free survival in cervical cancer.
  
  
  CONCLUSIONS
  High expression of either ULBP1 or MICA/B and ULBP1 combined is an indicator of good prognosis in cervical cancer, suggesting their potential utility as prognostic tests in clinical assessment.
authors.forename: Hanbyoul
authors.initials: H
authors.lastname: Cho
authors.forename: Joon-Yong
authors.initials: JY
authors.lastname: Chung
authors.forename: Sunghoon
authors.initials: S
authors.lastname: Kim
authors.forename: Till
authors.initials: T
authors.lastname: Braunschweig
authors.forename: Tae Heung
authors.initials: TH
authors.lastname: Kang
authors.forename: Jennie
authors.initials: J
authors.lastname: Kim
authors.forename: Eun Joo
authors.initials: EJ
authors.lastname: Chung
authors.affiliation: Department of Obstetrics and Gynecology, Gangnam Severance Hospital, Yonsei University College of Medicine, 146-92 Dogok-Dong, Gangnam-Gu, Seoul 135-720, Korea. genejock@helix.nih.gov.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.forename: Jae-Hoon
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor / Q000032:analysis*; D002352:Carrier Proteins / Q000032:analysis; D002584:Cervix Uteri / Q000737:chemistry; D018572:Disease-Free Survival; D005260:Female; D058851:GPI-Linked Proteins / Q000032:analysis; D006367:HeLa Cells; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000032:analysis; D047908:Intracellular Signaling Peptides and Proteins / Q000032:analysis*; D008024:Ligands; D008565:Membrane Proteins / Q000032:analysis; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K / Q000032:analysis*; D009367:Neoplasm Staging; D011379:Prognosis; D015996:Survival Rate; D046888:Tissue Array Analysis; D047368:Tumor Burden; D002583:Uterine Cervical Neoplasms / Q000737:chemistry* / Q000473:pathology; D002578:Uterine Cervical Dysplasia / Q000737:chemistry* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; D002352:Carrier Proteins; 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; D008565:Membrane Proteins; D055655:NK Cell Lectin-Like Receptor Subfamily K; C488760:RAET1E protein, human; C488761:RAET1G protein, human; C423231:ULBP1 protein, human; C423230:ULBP2 protein, human; C423229:ULBP3 protein, human