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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). Conclusion: 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. [ABSTRACT FROM AUTHOR]