In papillary thyroid carcinoma BRAFV600E is associated with increased expression of the urokinase plasminogen activator and its cognate receptor, but not with disease-free interval.
BACKGROUND
It has been suggested that patients with papillary thyroid cancer (PTC) harbouring the BRAF(V600E)  mutation have a worse prognosis. We showed in PTC that high levels of urokinase plasminogen activator (uPA) and its cognate receptor (uPAR) inversely correlate with disease-free interval (DFI).


OBJECTIVE
To investigate the effects of BRAF(V600E)  on the expression of uPA and uPAR and to evaluate the prognostic relevance of BRAF(V600E)  alone or in combination with uPA and uPAR. DESIGN/SETTING/PATIENTS/INTERVENTION: The case study included 91 patients with PTC. All patients underwent thyroidectomy and radioiodine therapy. Follow-up was available for 75 patients.


METHODS
The BRAF(V600E)  mutation was analysed by sequencing and mutant allele-specific PCR amplification; uPA and uPAR expression by quantitative RT-PCR.


RESULTS
BRAF(V600E)  was found in 44 of the 91 patients and associated with older age, but not with high-risk clinicopathological features. Urokinase PA and uPAR mRNA levels were higher in tumour tissues by 9·51 ± 1·30 and 4·64 ± 0·44 fold, respectively, compared to normal matched tissues, being significantly higher in BRAF(V600E) -positive patients. In vitro induction of BRAF(V600E)  in PCCL3 cells caused a significant increase in both uPA and uPAR mRNAs. Higher levels of uPA and uPAR correlated with lymph node metastases, TNM stage and disease recurrences. Kaplan-Meier and multivariate analyses demonstrated that uPA and uPAR were associated with shorter DFI, while the BRAF(V600E)  was not.


CONCLUSIONS
In PTC, BRAF(V600E)  induces uPA and uPAR expression. The latter, but not BRAF(V600E) , associates with advanced stages and shorter DFI. If confirmed in larger case studies, they may represent reliable prognostic markers for more accurate risk stratification and postoperative decision-making in patients with PTC.
Department of Experimental Medicine, University of Rome, Rome, Italy.
Salvatore
S
Ulisse
Enke
E
Baldini
Salvatore
S
Sorrenti
Susi
S
Barollo
Natalie
N
Prinzi
Antonio
A
Catania
Angela
A
Nesca
Lucio
L
Gnessi
Maria R
MR
Pelizzo
Caterina
C
Mian
Corrado
C
De Vito
Anna
A
Calvanese
Silvio
S
Palermo
Severino
S
Persechino
Enrico
E
De Antoni
Massimino
M
D'Armiento
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D002277:Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002291:Carcinoma, Papillary / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002460:Cell Line; D002648:Child; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D051381:Rats; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D014568:Urokinase-Type Plasminogen Activator / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
D055293:Receptors, Urokinase Plasminogen Activator; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D014568:Urokinase-Type Plasminogen Activator