title: Differential regulation of the human sodium/iodide symporter gene promoter in papillary thyroid carcinoma cell lines and normal thyroid cells.
abstract: The absence of TSH-stimulated radioiodide uptake in differentiated thyroid cancer is associated with a high recurrence rate and reduced survival. We studied regulation of the sodium/iodide symporter gene in human papillary thyroid cancer cell lines (BHP) and primary human thyroid cells. BHP cells expressed very low levels of sodium/iodide symporter mRNA and did not concentrate iodide, but iodide uptake was restored to levels seen in FRTL-5 rat thyroid cells by stable transfection of a sodium/iodide symporter cDNA. Sodium/iodide symporter gene expression, therefore, was necessary and sufficient for iodide uptake in BHP cells. We cloned the human sodium/iodide symporter gene 5'-flanking region and analyzed progressive 5'-deletions in transient transfections. We identified a region, -596 to -268, essential to confer full promoter activity in primary normal human thyroid cells. Sodium/iodide symporter promoter activity in four BHP cell lines, however, was markedly reduced, consistent with down-regulation of the endogenous sodium/iodide symporter gene. Nuclear extracts from BHP 2-7 cells had reduced or absent binding to regions of the sodium/iodide symporter promoter shown to be critical for expression, compared with nuclear extracts from FRTL-5 cells. Competition studies indicated that these nuclear proteins were not known thyroid transcription factors. Modifications of the sodium/iodide symporter promoter with demethylation or histone acetylation did not increase sodium/iodide symporter expression, and no deletions of the critical regulatory region were identified in the endogenous gene in BHP cells. Regulation of the sodium/iodide symporter 5'-flanking region in transient transfection paralleled endogenous sodium/iodide symporter expression. Reduced expression of potential novel nuclear factor(s) in these cell lines may contribute to reduced sodium/iodide symporter expression resulting in absence of iodide uptake in some papillary thyroid cancers.
authors.affiliation: The Endocrinology Division, VA Greater Los Angeles Healthcare System and Department of Medicine, UCLA School of Medicine, Los Angeles, California 90073, USA.
authors.forename: T
authors.initials: T
authors.lastname: Kogai
authors.forename: J M
authors.initials: JM
authors.lastname: Hershman
authors.forename: K
authors.initials: K
authors.lastname: Motomura
authors.forename: T
authors.initials: T
authors.lastname: Endo
authors.forename: T
authors.initials: T
authors.lastname: Onaya
authors.forename: G A
authors.initials: GA
authors.lastname: Brent
mesh_terms: D001483:Base Sequence / Q000235:genetics; D002291:Carcinoma, Papillary / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000378:metabolism; D017353:Gene Deletion; D015972:Gene Expression Regulation, Neoplastic; D016678:Genome; D006801:Humans; D007454:Iodides / Q000378:metabolism / Q000493:pharmacokinetics; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism / Q000502:physiology; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D010446:Peptide Fragments / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000502:physiology*; D012333:RNA, Messenger / Q000378:metabolism; D012016:Reference Values; D027981:Symporters; D013961:Thyroid Gland / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014407:Tumor Cells, Cultured; D000099209:Sodium-Iodide Symporters
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D007454:Iodides; D008565:Membrane Proteins; D009687:Nuclear Proteins; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors; D010446:Peptide Fragments; D012333:RNA, Messenger; D027981:Symporters; D000074482:Thyroid Nuclear Factor 1; D015534:Trans-Activators; D014157:Transcription Factors; D000099209:Sodium-Iodide Symporters; C083325:PAX8 protein, human