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).

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.

• Authors: Stefania Scarpino, Enrico Duranti, Simona Giglio, Arianna Di Napoli, Dino Galafate, Donatella Del Bufalo, Marianna Desideri, Fabio Socciarelli, Antonella Stoppacciaro, Luigi Ruco
• Journal: Thyroid : official journal of the American Thyroid Association (Thyroid) Vol. 23 Issue 9 Pg. 1127-37 (Sep 2013) ISSN: 1557-9077 [Electronic] United States
• PMID: 23617728 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CD82 protein, human
• Cyclooxygenase 2 Inhibitors
• Kangai-1 Protein
• Cyclooxygenase 2
• PTGS2 protein, human

Topics

• Adult
• Aged
• Animals
• Carcinoma (enzymology, genetics, secondary)
• Carcinoma, Papillary
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cyclooxygenase 2 (metabolism)
• Cyclooxygenase 2 Inhibitors (pharmacology)
• Female
• Humans
• Kangai-1 Protein (genetics, metabolism)
• Lymphatic Metastasis
• Male
• Mice, Nude
• Middle Aged
• Neoplasm Invasiveness
• Primary Cell Culture
• Signal Transduction
• Thyroid Cancer, Papillary
• Thyroid Neoplasms (enzymology, genetics, pathology)
• Transfection
• Tumor Cells, Cultured
• Young Adult