Expression of adenylyl cyclase types III and VI in human hyperfunctioning thyroid nodules

Celano, Marilena; Arturi, Franco; Presta, Ivan; Bruno, Rocco; Scarpelli, Daniela; Calvagno, Maria Grazia; Cristofaro, C.; Bulotta, Stefania; Giannasio, P.; Sacco, Rosario; Russo, Diego

doi:10.1016/s0303-7207(03)00086-8

Cited by 4 publications

(3 citation statements)

References 31 publications

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“…These genes are already up-regulated at 1.5 h and are still up-regulated after 48 h of TSH treatment; however, some are down-regulated in the adenomas. In autonomous adenomas, increased transcription of G proteincoupled receptor kinase 3 (GRK3) (46) and decreased transcription of some adenylate cyclases have similarly been reported (47). Together with the well described direct activation of some phosphodiesterases by cAMP-dependent kinases (48,49), these negative feedbacks, already described separately in various thyroid and other cell models (25,50), account for the well known biphasic character of the cAMP accumulation (1).…”

Section: Discussionmentioning

confidence: 86%

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Staveren¹,

Solís²,

Delys³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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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 Gs␣ activating mutations have been detected in thyroid autonomous adenomas, Gs␣ 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 oneshot 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.cyclic AMP ͉ microarrays ͉ papillary tumors ͉ thyrotropin T ight regulation of the second messenger cAMP is of crucial importance for cells because it regulates function, differentiation, and proliferation (1). In cells in which cAMP stimulates growth, activating mutations in partners of this pathway induce uncontrolled growth. In most benign thyroid autonomous adenomas, activating mutations have been found in the thyroidstimulating hormone (TSH) receptor (TSHR) (2) and, to a lesser extent, in the Gs␣ protein, an activator of the cAMP-producing adenylyl cyclase (1, 3). These mutations result in a TSHindependent growth and lead to hyperfunction (1). In addition, activating mutations of the Gs␣ protein have been detected in growth hormone-secreting pituitary adenomas (4) and inactivating mutations in the type I-␣ regulatory subunit inhibiting protein kinase A (PKAR1A) in Carney complex, a multiple neoplasia syndrome (5).Our knowledge of the genes regulated by the cAMP-protein kinase A cascade and its uncontrolled activation is still sketchy (6). To gain more insight into the cAMP-activated signal transduction cascade in tumors, human primary cultures of thyrocytes treated for different times with the TSH growth and differentiation stimulus were used as a model. Thyrocytes in primary culture are expected to be better mod...

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Section: Discussionmentioning

confidence: 86%

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Staveren¹,

Solís²,

Delys³

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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“…A proposed explanation may relate to the above-mentioned unknown alterations present in the TSHR-wt subgroup, which likely involve the same signal transduction pathways (cAMP or Ca-IP dependent) constitutively activated in the mutated group. Alternatively, activation of ''internal feedback loops'' in the TSHR-mut subgroup, involving adenylate cyclase, phosphodiesterase, or functional CREB expression, may counteract the effects of the mutations [29][30][31]. Finally, a role for environmental factors in addition to the genetic alterations may largely influence the gene expression profile as it acts on the full phenotype of the disease, as previously documented [32].…”

Section: Discussionmentioning

confidence: 93%

Increased expression of pro-angiogenic factors and vascularization in thyroid hyperfunctioning adenomas with and without TSH receptor activating mutations

et al. 2012

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Autonomously functioning thyroid nodules (AFTN) are known to receive an increased blood influx necessary to sustain their high rate of growth and hormone production. Here, we investigated the expression of hematic and lymphatic vases in a series of 20 AFTN compared with the contralateral non-tumor tissues of the same patients, and the transcript levels of proteins involved in the control of vascular proliferation, including the vascular endothelial growth factor (VEGF) and platelet-derived growth factors (PDGF) and their receptors and the endothelial nitric oxide synthase (eNOS). In parallel, the expression of the differentiation markers sodium/iodide symporter (NIS), thyroperoxidase (TPO), thyroglobulin (Tg), and TSH receptor (TSHR) was also investigated. The data were further analyzed comparing subgroups of tumors with or without mutations in the TSHR gene. Analysis by means of CD31 and D2-40 immunostaining showed in AFTN an increased number of hematic, but not lymphatic, vessels in parallel with an enhanced proliferation rate shown by increased Ki67 staining. Quantitative RT-PCR analysis revealed an increase of VEGF, VEGFR1 and 2, PDGF-A, PDGF-B, and eNOS expression in tumor versus normal tissues. Also, higher transcript levels of NIS, TPO, and Tg were detected. Comparison of the two subgroups of samples revealed only few differences in the expression of the genes examined. In conclusion, these data demonstrate an increased expression of angiogenesis-related factors associated with an enhanced proliferation of hematic, but not lymphatic, vessels in AFTNs. In this context, the presence of TSHR mutations may only slightly influence the expression of pro-angiogenic growth factors.

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“…No information is available in the literature on ADCY6 expression in head and neck cancer. However, Celano et al (38) observed that its expression is significantly lower in hyperfunctioning thyroid tumors than in normal thyroid tissue, evidencing a low expression of this gene in transformed tissues.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling reveals molecular marker candidates of laryngeal squamous cell carcinoma

Colombo

Fachel²,

Calmon³

et al. 2009

Oncol Rep

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Expression of adenylyl cyclase types III and VI in human hyperfunctioning thyroid nodules

Cited by 4 publications

References 31 publications

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Gene expression in human thyrocytes and autonomous adenomas reveals suppression of negative feedbacks in tumorigenesis

Increased expression of pro-angiogenic factors and vascularization in thyroid hyperfunctioning adenomas with and without TSH receptor activating mutations

Gene expression profiling reveals molecular marker candidates of laryngeal squamous cell carcinoma

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