title: Papillary carcinoma of the thyroid: high expression of COX-2 and low expression of KAI-1/CD82 are associated with increased tumor invasiveness.
abstract: BACKGROUND
  We have previously demonstrated that expression of COX-2 is upregulated by hepatocyte growth factor in thyroid papillary carcinoma (TPC) cells and is associated with increased invasiveness of tumor cells. COX-2 upregulation was associated with downregulation of KAI-1/CD82, a metastasis suppressor molecule that has been associated with the metastatic potential of several solid tumors. In the present study, we have investigated the possibility that downregulation of KAI-1/CD82 may contribute to the invasiveness of papillary carcinoma cells.
  
  
  METHODS
  Expression of KAI-1/CD82 and its relation to COX-2 levels were investigated in 6 primary cultures of TPC, in 2 tumor cell lines (TPC-1 and K1), and in 55 tumor samples of TPC. The biological role of KAI-1/CD82 in regulating tumor invasiveness was investigated in TPC cell lines and primary cultures transfected with a pCDNA3.1/Hygro.KAI-1; transfected cells were tested in functional studies of cell migration and invasiveness. Finally, the role of KAI-1/CD82 in influencing TPC metastasis was investigated in vivo using nu/nu mice injected with K1-transfected cells.
  
  
  RESULTS
  We provide evidence that COX-2 and KAI-1/CD82 are inversely regulated in TPC primary cultures and in TPC-1 tumor cells. In fact, inhibition of COX-2 with NS398 is associated with a 2-9-fold upregulation of KAI-1/CD82 RNA. Moreover, a possible relation between COX-2 and KAI-1/CD82 was confirmed by the presence of a statistically significant inverse correlation in the expression of the two genes in 55 tumor samples of TPC (r = -0.513; p = 0.001). In 36 of 55 cases, tumor areas contained lower levels of KAI-1/CD82 RNA as compared with the corresponding normal tissue. Low expression of KAI-1/CD82 RNA in the tumor area was associated with extrathyroid extension of the disease in 16 of 19 cases (p < 0.04) and with lymph node metastasis in 11 of 14 cases (not significant). KAI-1/CD82 re-expression in tumor cells was associated with a significant decrease in their migratory (50-76% reduction) and invasive (46-65% reduction) capacity, even after hepatocyte growth factor stimulation. Finally, nu/nu mice injected with KAI-1/CD82-transfected K1 TPC cells developed fewer and smaller metastasis as compared with mice injected with vector-transfected K1 cells (p=0.016).
  
  
  CONCLUSIONS
  Our findings raise the possibility that downregulation of KAI-1/CD82 in TPC cells is one of the molecular mechanisms regulating their invasive and metastatic potential.
authors.affiliation: 1 Department of Clinical and Molecular Medicine, "Sapienza" University, Sant'Andrea Hospital, Rome, Italy .
authors.forename: Stefania
authors.initials: S
authors.lastname: Scarpino
authors.forename: Enrico
authors.initials: E
authors.lastname: Duranti
authors.forename: Simona
authors.initials: S
authors.lastname: Giglio
authors.forename: Arianna
authors.initials: A
authors.lastname: Di Napoli
authors.forename: Dino
authors.initials: D
authors.lastname: Galafate
authors.forename: Donatella
authors.initials: D
authors.lastname: Del Bufalo
authors.forename: Marianna
authors.initials: M
authors.lastname: Desideri
authors.forename: Fabio
authors.initials: F
authors.lastname: Socciarelli
authors.forename: Antonella
authors.initials: A
authors.lastname: Stoppacciaro
authors.forename: Luigi
authors.initials: L
authors.lastname: Ruco
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D002277:Carcinoma / Q000201:enzymology* / Q000235:genetics / Q000556:secondary; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D051861:Kangai-1 Protein / Q000235:genetics / Q000378:metabolism*; D008207:Lymphatic Metastasis; D008297:Male; D008819:Mice, Nude; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D061251:Primary Cell Culture; D015398:Signal Transduction; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D014162:Transfection; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: C497688:CD82 protein, human; D052246:Cyclooxygenase 2 Inhibitors; D051861:Kangai-1 Protein; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human