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.

Abstract

CONTEXT:

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).

OBJECTIVES:

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.

MAIN OUTCOME MEASURES:

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.

CONCLUSION:

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.

• Authors: Salvatore Ulisse, Enke Baldini, Salvatore Sorrenti, Susi Barollo, Natalie Prinzi, Antonio Catania, Angela Nesca, Lucio Gnessi, Maria R Pelizzo, Caterina Mian, Corrado De Vito, Anna Calvanese, Silvio Palermo, Severino Persechino, Enrico De Antoni, Massimino D'Armiento
• Journal: Clinical endocrinology (Clin Endocrinol (Oxf)) Vol. 77 Issue 5 Pg. 780-6 (Nov 2012) ISSN: 1365-2265 [Electronic] England
• PMID: 22702340 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2012 Blackwell Publishing Ltd.

Chemical References

• Receptors, Urokinase Plasminogen Activator
• BRAF protein, human
• Proto-Oncogene Proteins B-raf
• Urokinase-Type Plasminogen Activator

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Animals
• Carcinoma (genetics, metabolism, pathology)
• Carcinoma, Papillary (genetics, metabolism, pathology)
• Cell Line
• Child
• Female
• Humans
• Male
• Middle Aged
• Polymerase Chain Reaction
• Proto-Oncogene Proteins B-raf (genetics)
• Rats
• Receptors, Urokinase Plasminogen Activator (genetics, metabolism)
• Thyroid Cancer, Papillary
• Thyroid Neoplasms (genetics, metabolism, pathology)
• Urokinase-Type Plasminogen Activator (genetics, metabolism)
• Young Adult