title: Osteoprotegerin (OPG) and related proteins (RANK, RANKL and TRAIL) in thyroid disease.
abstract: BACKGROUND
  Osteoprotegerin (OPG), receptor activator of nuclear factor kappaB (RANK), RANK ligand (RANKL), and TNF related apoptosis inducing ligand (TRAIL) are the key proteins in the development of bone metastases. Osteoprotegerin improves tumor cell survival and inhibits TRAIL induced apoptosis of cancer cell lines. It also binds to RANKL and inhibits its interaction with RANK (cell surface receptor), which influences osteoclast formation and function. The aim of the present study was to characterize the expression of OPG, RANK, RANKL, and TRAIL in benign and malignant thyroid tissue and thyroid cell lines.
  
  
  METHODS
  Archived thyroid tissue from 79 patients (60 differentiated thyroid cancers and 19 benign thyroids) was stained for OPG, RANK, RANKL, and TRAIL by immunohistochemistry. Staining was assessed semiquantitatively and correlated with pathology. Western blots were performed on three human thyroid cell lines: Nthy-ori 3-1 (thyroid follicular epithelium), FTC-133 (follicular thyroid carcinoma), and K1E7 (subclone of papillary thyroid carcinoma).
  
  
  RESULTS
  Osteoprotegerin and RANKL staining was cytoplasmic; RANK staining was nuclear; and TRAIL staining was predominantly cytoplasmic. All four proteins were expressed in benign and malignant tissue. There was significant difference in RANK expression between malignant and benign tissue (8 vs. 84%, respectively; Fisher's exact test; P < 0.001). RANKL expression was significantly increased in malignant tissue (Fisher's exact test; P = 0.04). Western blotting showed OPG expression in all cell lines and TRAIL in none. RANK and RANKL were not detected in papillary and follicular cell lines, respectively.
  
  
  CONCLUSIONS
  Nuclear expression of RANK protein in thyroid tissue is paradoxical; it could be due to nuclear migration after ligand binding. Suppression of RANK and increased expression of RANKL in malignant tissue warrant further investigation.
authors: Department of Oncology, University of Sheffield, Sheffield, UK. timusdoos@yahoo.com
authors: Sumit K
authors: SK
authors: Sood
authors: Sabapathy
authors: S
authors: Balasubramanian
authors: Sue
authors: S
authors: Higham
authors: Malee
authors: M
authors: Fernando
authors: Barney
authors: B
authors: Harrison
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000032:analysis* / Q000235:genetics; D001707:Biopsy, Needle; D015153:Blotting, Western; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D015588:Observer Variation; D053244:Osteoprotegerin / Q000032:analysis* / Q000235:genetics; D053245:RANK Ligand / Q000032:analysis* / Q000235:genetics; D012189:Retrospective Studies; D018570:Risk Assessment; D012680:Sensitivity and Specificity; D018709:Statistics, Nonparametric; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000032:analysis* / Q000235:genetics; D013959:Thyroid Diseases / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D013964:Thyroid Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000601:surgery; D013965:Thyroidectomy / Q000379:methods; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D053244:Osteoprotegerin; D053245:RANK Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human