title: Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis.
abstract: The cAMP signaling pathway regulates growth of many cell types, including somatotrophs, thyrocytes, melanocytes, ovarian follicular granulosa cells, adrenocortical cells, and keratinocytes. Mutations of partners from the cAMP signaling cascade are involved in tumor formation. Thyroid-stimulating hormone (TSH) receptor and Gsalpha activating mutations have been detected in thyroid autonomous adenomas, Gsalpha mutations in growth hormone-secreting pituitary adenomas, and PKAR1A mutations in Carney complex, a multiple neoplasia syndrome. To gain more insight into the role of cAMP signaling in tumor formation, human primary cultures of thyrocytes were treated for different times (1.5, 3, 16, 24, and 48 h) with TSH to characterize modulations in gene expression using cDNA microarrays. This kinetic study showed a clear difference in expression, early (1.5 and 3 h) and late (16-48 h) after the onset of TSH stimulation. This result suggests a progressive sequential process leading to a change of cell program. The gene expression profile of the long-term stimulated cultures resembled the autonomous adenomas, but not papillary carcinomas. The molecular phenotype of the adenomas thus confirms the role of long-term stimulation of the TSH-cAMP cascade in the pathology. TSH induced a striking up-regulation of different negative feedback modulators of the cAMP cascade, presumably insuring the one-shot effect of the stimulus. Some were down- or nonregulated in adenomas, suggesting a loss of negative feedback control in the tumors. These results suggest that in tumorigenesis, activation of proliferation pathways may be complemented by suppression of multiple corresponding negative feedbacks, i.e., specific tumor suppressors.
authors.affiliation: Institute of Interdisciplinary Research (IRIBHM), School of Medicine, Belgium.
authors.forename: Wilma C G
authors.initials: WC
authors.lastname: van Staveren
authors.forename: David Weiss
authors.initials: DW
authors.lastname: Solís
authors.forename: Laurent
authors.initials: L
authors.lastname: Delys
authors.forename: David
authors.initials: D
authors.lastname: Venet
authors.forename: Matteo
authors.initials: M
authors.lastname: Cappello
authors.forename: Guy
authors.initials: G
authors.lastname: Andry
authors.forename: Jacques E
authors.initials: JE
authors.lastname: Dumont
authors.forename: Frédérick
authors.initials: F
authors.lastname: Libert
authors.forename: Vincent
authors.initials: V
authors.lastname: Detours
authors.forename: Carine
authors.initials: C
authors.lastname: Maenhaut
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology*; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics* / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics; D025461:Feedback, Physiological; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007700:Kinetics; D020411:Oligonucleotide Array Sequence Analysis; D012333:RNA, Messenger / Q000235:genetics; D013961:Thyroid Gland / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology*; D013972:Thyrotropin / Q000494:pharmacology; D013997:Time Factors; D014407:Tumor Cells, Cultured
chemical_list: D012333:RNA, Messenger; D013972:Thyrotropin