Potent mitogenicity of the RET/PTC3 oncogene correlates with its prevalence in tall-cell variant of papillary thyroid carcinoma.
The tall-cell variant (TCV) of papillary thyroid carcinoma (PTC), characterized by tall cells bearing an oxyphilic cytoplasm, is more clinically aggressive than conventional PTC. RET tyrosine kinase rearrangements, which represent the most frequent genetic alteration in PTC, lead to the recombination of RET with heterologous genes to generate chimeric RET/PTC oncogenes. RET/PTC1 and RET/PTC3 are the most prevalent variants. We have found RET rearrangements in 35.8% of TCV (14 of 39 cases). Whereas the prevalences of RET/PTC1 and RET/PTC3 were almost equal in classic and follicular PTC, all of the TCV-positive cases expressed the RET/PTC3 rearrangement. These findings prompted us to compare RET/PTC3 and RET/PTC1 in an in vitro thyroid model system. We have expressed the two oncogenes in PC Cl 3 rat thyroid epithelial cells and found that RET/PTC3 is endowed with a strikingly more potent mitogenic effect than RET/PTC1. Mechanistically, this difference correlated with an increased signaling activity of RET/PTC3. In conclusion, we postulate that the correlation between the RET/PTC rearrangement type and the aggressiveness of human PTC is related to the efficiency with which the oncogene subtype delivers mitogenic signals to thyroid cells.
Basolo
Fulvio
F
Dipartimento di Oncologia, Università degli Studi di Pisa, Pisa. Fondazione Senatore Pascale, Naples, Italy. fbasolo@do.med.unipi.it
Giannini
Riccardo
R
Monaco
Carmen
C
Melillo
Rosa Marina
RM
Carlomagno
Francesca
F
Pancrazi
Martina
M
Salvatore
Giuliana
G
Chiappetta
Gennaro
G
Pacini
Furio
F
Elisei
Rossella
R
Miccoli
Paolo
P
Pinchera
Aldo
A
Fusco
Alfredo
A
Santoro
Massimo
M
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000473:pathology*; D002460:Cell Line; D002648:Child; D005260:Female; D005787:Gene Frequency; D006133:Growth Substances / Q000502:physiology*; D006801:Humans; D008297:Male; D008875:Middle Aged; D015514:Oncogene Proteins, Fusion / Q000502:physiology; D009857:Oncogenes / Q000502:physiology*; D010749:Phosphoprotein Phosphatases / Q000235:genetics* / Q000502:physiology; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C; D011505:Protein-Tyrosine Kinases; D051381:Rats; D011916:Rats, Inbred F344; D029701:Saccharomyces cerevisiae Proteins; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*
D006133:Growth Substances; D015514:Oncogene Proteins, Fusion; D029701:Saccharomyces cerevisiae Proteins; D011505:Protein-Tyrosine Kinases; C093573:ret-PTC fusion oncoproteins, human; C087358:PTC1 protein, S cerevisiae; C000607464:PTC3 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D054648:Protein Phosphatase 2; D000071636:Protein Phosphatase 2C