Human telomerase reverse transcriptase in papillary thyroid cancer: gene expression, effects of silencing and regulation by BET inhibitors in thyroid cancer cells

• Published in: Endocrine Vol. 63; no. 3; pp. 545 - 553
• Main Authors: Maggisano, Valentina, Celano, Marilena, Lepore, Saverio Massimo, Sponziello, Marialuisa, Rosignolo, Francesca, Pecce, Valeria, Verrienti, Antonella, Baldan, Federica, Mio, Catia, Allegri, Lorenzo, Maranghi, Marianna, Falcone, Rosa, Damante, Giuseppe, Russo, Diego, Bulotta, Stefania
• Format: Journal Article
• Language: English
• Published: New York Springer US 01.03.2019; Springer Nature B.V
• Subjects: Adult; Aged; AKT protein; Azepines; Benzodiazepines; Cell Line, Tumor; Cell viability; Diabetes; Endocrinology; Female; Gene expression; Humanities and Social Sciences; Humans; Internal Medicine; Male; Medicine; Medicine & Public Health; Middle Aged; multidisciplinary; Mutation; Original Article; Papillary thyroid cancer; Phosphorylation; Proteins - antagonists & inhibitors; RNA-directed DNA polymerase; RNA-mediated interference; Science; Telomerase - antagonists & inhibitors; Telomerase - metabolism; Telomerase reverse transcriptase; Therapeutic applications; Thyroid cancer; Thyroid Cancer, Papillary - enzymology; Thyroid Neoplasms - enzymology; Triazoles; Tumors; Young Adult; β-Catenin; siRNA anti; phospho-AKT; Papillary thyroid cancer; BET inhibitors; siRNA anti-hTERT
• ISSN: 1355-008X; 1559-0100
• DOI: 10.1007/s12020-018-01836-2

Purpose Mutations in TERT promoter have been detected in the more aggressive papillary thyroid cancers (PTCs). To elucidate the role of TERT as an eligible molecular target in these tumors, the expression of hTERT was analyzed in a series of PTCs and the effects of both pharmacological and RNA-interference-induced hTERT silencing were investigated in two human PTC cell lines (K1 and BCPAP). Methods The expression levels of hTERT mRNA and protein were evaluated by real-time PCR and western blot assays, respectively. Effects of hTERT silencing on PTC cell lines were analyzed by MTT, migration and western blot assays. Pharmacological inhibition of hTERT was performed using two bromodomain and extra-terminal (BET) inhibitors, JQ1 and I-BET762. Results hTERT expression results increased in 20 out of 48 PTCs, including tumors either positive or negative for the presence of hTERT promoter and/or BRAF mutations. In K1 and BCPAP cells, hTERT silencing determined a reduction in cell viability (~50% for K1 and ~70%, for BCPAP, vs control) and migration properties that were associated with a decrease of AKT phosphorylation and β-Catenin expression. Moreover, hTERT mRNA levels were down-regulated by two BET inhibitors, JQ1 and I-BET762, which at the same dosage (0.5 and 5 µM) reduced the growth of these thyroid cancer cells. Conclusions These findings demonstrate that hTERT may represent an excellent therapeutic target in subgroups of aggressive PTCs.