title: Different expression of TSH receptor and NIS genes in thyroid cancer: role of epigenetics.
abstract: The TSH receptor (TSHR) and sodium/iodide symporter (NIS) are key players in radioiodine-based treatment of differentiated thyroid cancers. While NIS (SLC5AS) expression is diminished/lost in most thyroid tumors, TSHR is usually preserved. To examine the mechanisms that regulate the expression of NIS and TSHR genes in thyroid tumor cells, we analyzed their expression after inhibition of ras-BRAF-MAPK and PI3K-Akt-mTOR pathways and the epigenetic control occurring at the gene promoter level in four human thyroid cancer cell lines. Quantitative real-time PCR was used to measure NIS and TSHR mRNA in thyroid cancer cell lines (TPC-1, BCPAP, WRO, and FTC-133). Western blotting was used to assess the levels of total and phosphorylated ERK and Akt. Chromatin immunoprecipitation was performed for investigating histone post-translational modifications of the TSHR and NIS genes. ERK and Akt inhibitors elicited different responses of the cells in terms of TSHR and NIS mRNA levels. Akt inhibition increased NIS transcript levels and reduced those of TSHR in FTC-133 cells but had no significant effects in BCPAP. ERK inhibition increased the expression of both genes in BCPAP cells but had no effects in FTC-133. Histone post-translational modifications observed in the basal state of the four cell lines as well as in BCPAP treated with ERK inhibitor and FTC-133 treated with Akt inhibitor show cell- and gene-specific differences. In conclusion, our data indicate that in thyroid cancer cells the expression of TSHR and NIS genes is differently controlled by multiple mechanisms, including epigenetic events elicited by major signaling pathways involved in thyroid tumorigenesis.
authors.affiliation: Department of Health Sciences, University of Catanzaro 'Magna Graecia', Campus 'S. Venuta', Viale Europa, Germaneto, 88100 Catanzaro, Italy Departments of Internal Medicine and Medical Specialties Surgical Sciences, University of Roma 'Sapienza', 00161 Roma, Italy Department of Medical and Biological Sciences, University of Udine, 33100 Udine, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: D'Agostino
authors.forename: Marialuisa
authors.initials: M
authors.lastname: Sponziello
authors.forename: Cinzia
authors.initials: C
authors.lastname: Puppin
authors.forename: Marilena
authors.initials: M
authors.lastname: Celano
authors.forename: Valentina
authors.initials: V
authors.lastname: Maggisano
authors.forename: Federica
authors.initials: F
authors.lastname: Baldan
authors.forename: Marco
authors.initials: M
authors.lastname: Biffoni
authors.forename: Stefania
authors.initials: S
authors.lastname: Bulotta
authors.forename: Cosimo
authors.initials: C
authors.lastname: Durante
authors.forename: Sebastiano
authors.initials: S
authors.lastname: Filetti
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Damante
authors.forename: Diego
authors.initials: D
authors.lastname: Russo
mesh_terms: D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D044127:Epigenesis, Genetic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006657:Histones / Q000378:metabolism; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009928:Organ Specificity / Q000187:drug effects / Q000235:genetics; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011989:Receptors, Thyrotropin / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D000099209:Sodium-Iodide Symporters
chemical_list: D006657:Histones; D020929:Mitogen-Activated Protein Kinase Kinases; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011989:Receptors, Thyrotropin; D027981:Symporters; D000099209:Sodium-Iodide Symporters
keywords: Akt; MAPK; NIS; TSH receptor; epigenetics; thyroid cancer