COX-2 is induced by HGF stimulation in Met-positive thyroid papillary carcinoma cells and is involved in tumour invasiveness

J Pathol. 2009 Aug;218(4):487-94. doi: 10.1002/path.2556.

Abstract

Thyroid papillary carcinoma (TPC) cells express high levels of cytoplasmic cyclo-oxygenase 2 protein. Analysis of microdissected samples of the tumour and of the paired normal thyroid tissue confirmed that mRNA transcripts for cyclo-oxygenase 2 (COX-2) were significantly more numerous in the tumour (7.6 +/- 13-fold; p = 0.01). High levels of COX-2 mRNA were not associated with age, sex, tumour size or lymph node metastasis. COX-2 was not homogeneously expressed throughout the tumour, but was significantly higher at the tumour invasion front. Hepatocyte growth factor (HGF) can up-regulate the expression of COX-2 mRNA. A marked increase in COX-2 mRNA levels was observed in 8/8 primary TPC cultures after HGF stimulation (6.3 +/- 6-fold) and in two papillary carcinoma cell lines (TPC-1 and NPA). Specific involvement of the high-affinity HGF receptor (Met protein) was suggested by the observation that PHA-665752, an inhibitor of the catalytic activity of c-Met kinase, caused a 54% reduction of the hepatocyte growth factor-induced COX-2 up-regulation. The possibility that HGF-Met interactions also had a causative role in the up-regulation of COX-2 in vivo was investigated in 30 tumour samples, where it was found that there was a statistically significant correlation (p = 0.001, r = 0.85) in the levels of expression of MET and COX-2 RNAs. The biological role of COX-2 in TPC cells was investigated by treating the TPC cell lines with the specific COX-2 inhibitor NS-398. It was found that NS-398 treatment significantly reduced the migration (50-75%) and invasiveness (47-92%) of tumour cells, but did not alter cell proliferation. Our data suggest that the increased expression of Met protein in TPC cells has a role in up-regulating the expression of COX-2, which in turn contributes to the invasive capacity of TPC cells.

MeSH terms

  • Adult
  • Aged
  • Blotting, Western / methods
  • Carcinoma, Papillary / enzymology*
  • Carcinoma, Papillary / genetics
  • Cell Line, Tumor
  • Cyclooxygenase 2 / analysis
  • Cyclooxygenase 2 / genetics
  • Cyclooxygenase 2 / metabolism*
  • Female
  • Gene Expression Regulation, Neoplastic / drug effects*
  • Hepatocyte Growth Factor / pharmacology*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • RNA, Messenger / analysis
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Statistics, Nonparametric
  • Thyroid Neoplasms / enzymology*
  • Thyroid Neoplasms / genetics
  • Tumor Cells, Cultured
  • Up-Regulation*

Substances

  • RNA, Messenger
  • Hepatocyte Growth Factor
  • Cyclooxygenase 2
  • PTGS2 protein, human