COX-2 is induced by HGF stimulation in Met-positive thyroid papillary carcinoma cells and is involved in tumour invasiveness.
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.
Scarpino
Stefania
S
Dipartimento di Medicina Sperimentale, II Facoltà di Medicina e Chirurgia, Ospedale Sant'Andrea, Università La Sapienza, Roma, Italy. stefania.scarpino@uniroma1.it
Duranti
Enrico
E
Stoppacciaro
Antonella
A
Pilozzi
Emanuela
E
Natoli
Guido
G
Sciacchitano
Salvatore
S
Luciani
Emidio
E
Ruco
Luigi
L
D000328:Adult; D000368:Aged; D015153:Blotting, Western / Q000379:methods; D002291:Carcinoma, Papillary / Q000201:enzymology* / Q000235:genetics; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D012333:RNA, Messenger / Q000032:analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D018709:Statistics, Nonparametric; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D012333:RNA, Messenger; D017228:Hepatocyte Growth Factor; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human