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Published on: August 23, 2019
Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in
Wilma C G van Staveren1, David Weiss Solís, Laurent Delys
1Institute of Interdisciplinary Research (IRIBHM), School of Medicine, Belgium.
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.
Insights
Thyroid-stimulating hormone (TSH) activates the cAMP pathway, influencing cell growth and tumor formation. Long-term TSH stimulation in thyrocytes mimics gene expression in thyroid adenomas, suggesting a loss of negative feedback in tumor development.
Area of Science:
- Molecular Biology
- Cellular Signaling
- Oncology
Background:
- The cyclic adenosine monophosphate (cAMP) signaling pathway is crucial for regulating the growth of various cell types.
- Dysregulation of the cAMP pathway and its associated proteins is implicated in the development of several human tumors, including thyroid adenomas and pituitary adenomas.
- Mutations in key signaling components like the TSH receptor, Gsalpha, and PKAR1A are linked to specific neoplastic conditions.
Purpose of the Study:
- To investigate the role of cAMP signaling in tumor formation by examining gene expression changes in human thyrocytes upon TSH stimulation.
- To characterize the temporal dynamics of gene expression modulation in response to TSH.
- To compare the molecular phenotype of TSH-stimulated thyrocytes with that of thyroid tumors.
Main Methods:
- Primary human thyrocyte cultures were treated with TSH for varying durations (1.5, 3, 16, 24, and 48 hours).
- Gene expression profiles were analyzed using cDNA microarrays to identify modulated genes.
- Kinetic analysis was performed to distinguish early and late responses to TSH stimulation.
Main Results:
- TSH stimulation induced distinct early and late gene expression patterns, indicating a sequential cellular response.
- Long-term TSH stimulation resulted in a gene expression profile similar to that observed in autonomous thyroid adenomas, but not papillary carcinomas.
- TSH significantly upregulated negative feedback regulators of the cAMP cascade, which were found to be downregulated or non-regulated in adenomas, suggesting impaired negative feedback in tumors.
Conclusions:
- Long-term activation of the TSH-cAMP cascade plays a significant role in the pathogenesis of thyroid autonomous adenomas.
- Tumorigenesis may involve the simultaneous activation of proliferation pathways and the suppression of negative feedback mechanisms, acting as tumor suppressors.
- Understanding these molecular dynamics provides insights into the development of cAMP-mediated tumors.
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