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

• Published in: Clinical endocrinology (Oxford) Vol. 77; no. 5; pp. 780 - 786
• Main Authors: Ulisse, Salvatore, Baldini, Enke, Sorrenti, Salvatore, Barollo, Susi, Prinzi, Natalie, Catania, Antonio, Nesca, Angela, Gnessi, Lucio, Pelizzo, Maria R., Mian, Caterina, De Vito, Corrado, Calvanese, Anna, Palermo, Silvio, Persechino, Severino, De Antoni, Enrico, D'Armiento, Massimino
• Format: Journal Article
• Language: English
• Published: Oxford Blackwell Publishing Ltd 01.11.2012; Blackwell; Wiley Subscription Services, Inc
• Subjects: Adolescent; Adult; Aged; Aged, 80 and over; Animals; Biological and medical sciences; Carcinoma - genetics; Carcinoma - metabolism; Carcinoma - pathology; Carcinoma, Papillary - genetics; Carcinoma, Papillary - metabolism; Carcinoma, Papillary - pathology; Cell Line; Child; Endocrinopathies; Female; Fundamental and applied biological sciences. Psychology; General aspects; Humans; Male; Malignant tumors; Medical sciences; Middle Aged; Polymerase Chain Reaction; Proto-Oncogene Proteins B-raf - genetics; Rats; Receptors, Urokinase Plasminogen Activator - genetics; Receptors, Urokinase Plasminogen Activator - metabolism; Thyroid Cancer, Papillary; Thyroid Neoplasms - genetics; Thyroid Neoplasms - metabolism; Thyroid Neoplasms - pathology; Thyroid. Thyroid axis (diseases); Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; Vertebrates: endocrinology; Young Adult; Endocrinopathy; u-Plasminogen activator; Serine endopeptidases; Disease; Enzyme; Thyroid diseases; Malignant tumor; Gene expression; Peptidases; Association; Hydrolases; Papillary thyroid carcinoma; Endocrinology; Cancer
• ISSN: 0300-0664; 1365-2265
• DOI: 10.1111/j.1365-2265.2012.04465.x

Summary Context It has been suggested that patients with papillary thyroid cancer (PTC) harbouring the BRAFV600E 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). Objectives To investigate the effects of BRAFV600E on the expression of uPA and uPAR and to evaluate the prognostic relevance of BRAFV600E 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. Main outcome measures The BRAFV600E mutation was analysed by sequencing and mutant allele‐specific PCR amplification; uPA and uPAR expression by quantitative RT‐PCR. Results BRAFV600E 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 BRAFV600E‐positive patients. In vitro induction of BRAFV600E 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 BRAFV600E was not. Conclusion In PTC, BRAFV600E induces uPA and uPAR expression. The latter, but not BRAFV600E, 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.