title: PDE5 expression in human thyroid tumors and effects of PDE5 inhibitors on growth and migration of cancer cells.
abstract: Recent studies have revealed in normal thyroid tissue the presence of the transcript of several phosphodiesterases (PDEs), enzymes responsible for the hydrolysis of cyclic nucleotides. In this work, we analyzed the expression of PDE5 in a series of human papillary thyroid carcinomas (PTCs) presenting or not BRAF V600E mutation and classified according to ATA risk criteria. Furthermore, we tested the effects of two PDE5 inhibitors (sildenafil, tadalafil) against human thyroid cancer cells. PDE5 gene and protein expression were analyzed in two different cohorts of PTCs by real-time PCR using a TaqMan micro-fluid card system and Western blot. MTT and migration assay were used to evaluate the effects of PDE5 inhibitors on proliferation and migration of TPC-1, BCPAP, and 8505C cells. In a first series of 36 PTCs, we found higher expression levels of PDE5A in tumors versus non-tumor (normal) tissues. PTCs with BRAF mutation showed higher levels of mRNA compared with those without mutation. No significant differences were detected between subgroups with low and intermediate ATA risk. Upregulation of PDE5 was also detected in tumor tissue proteins. Similar results were obtained analyzing the second cohort of 50 PTCs. Moreover, all tumor tissues with high PDE5 levels showed reduction of Thyroglobulin, TSH receptor, Thyroperoxidase, and NIS transcripts. In thyroid cancer cells in vitro, sildenafil and tadalafil determined a reduction of proliferation and cellular migration. Our findings demonstrate for the first time an overexpression of PDE5 in PTCs, and the ability of PDE5 inhibitors to block the proliferation of thyroid cancer cells in culture, therefore, suggesting that specific inhibition of PDE5 may be proposed for the treatment of these tumors.
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Antonella
authors.initials: A
authors.lastname: Verrienti
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Rosignolo
authors.affiliation: Department of Health Sciences, University of Catanzaro "Magna Graecia", Campus "S. Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Roberta Francesca
authors.initials: RF
authors.lastname: De Rose
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Valeria
authors.initials: V
authors.lastname: Pecce
authors.affiliation: Department of Health Sciences, University of Catanzaro "Magna Graecia", Campus "S. Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Maggisano
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.affiliation: Department of Health Sciences, University of Catanzaro "Magna Graecia", Campus "S. Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Bulotta
authors.affiliation: Institute of Medical Genetics, University Hospital "S. Maria della Misericordia", 33100, Udine, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
authors.affiliation: Department of Surgical Sciences, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Giacomelli
authors.affiliation: Department of Radiological, Oncological and Pathological Sciences, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Cira Rosaria Tiziana
authors.initials: CR
authors.lastname: Di Gioia
authors.affiliation: Department of Internal Medicine and Medical Specialties, University of Rome "Sapienza", 00161, Rome, Italy.
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
authors.affiliation: Department of Health Sciences, University of Catanzaro "Magna Graecia", Campus "S. Venuta", Viale Europa, 88100, Catanzaro, Italy. d.russo@unicz.it.
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
authors.affiliation: Department of Health Sciences, University of Catanzaro "Magna Graecia", Campus "S. Venuta", Viale Europa, 88100, Catanzaro, Italy.
authors.forename: Marilena
authors.initials: M
authors.lastname: Celano
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002277:Carcinoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D002291:Carcinoma, Papillary; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D000068677:Sildenafil Citrate / Q000494:pharmacology*; D000068581:Tadalafil / Q000494:pharmacology*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D055815:Young Adult
chemical_list: D058986:Phosphodiesterase 5 Inhibitors; D000068581:Tadalafil; D000068677:Sildenafil Citrate; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; C517381:PDE5A protein, human
keywords: BRAF; Papillary thyroid carcinoma; Phosphodiesterases; Thyroid cancer cells
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