Immunohistochemical expression of cyclin D1, E2F‐1, and Ki‐67 in benign and malignant thyroid lesions

Ayala, Antonio Saiz; Olvera, Maria; Rezk, Sherif; Florentine, Barbara A.; McCourty, Althea; Brynes, Russell K.

doi:10.1002/path.1185

Cited by 81 publications

(61 citation statements)

References 20 publications

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“…One puzzling common property of autonomous adenomas and papillary carcinomas is the down-regulation of a number of immediate early genes [NR4A1, JUNB (10), KLF10, and ZFP36]. Absence of upregulation may reflect the relatively low rate of cell proliferation in both tumors (42,43) and thus the low fraction of cells in early G 1 , but down-regulation is more difficult to explain.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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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“…However, it is necessary to point out that cyclin D3 may not be the only determinant of thyrocyte proliferation in human thyroid hyperproliferative diseases, since previous works have demonstrated that cyclin D1 is overexpressed in hyperplastic nodules and adenomas (Saiz et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland

Motti

Boccia

Belletti³

et al. 2003

Oncogene

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We report that cyclin D3 is rate limiting for G1 progression in thyroid follicular cells and that its constitutive upregulation by chronic stimulation of the TSH/cAMP pathway plays a role in human and experimental hyperproliferative diseases of the thyroid gland. These conclusions are supported by in vitro and in vivo studies. In rat thyrocytes (PC Cl 3 cells), cyclin D3 expression is enhanced in response to activation of the TSH/cAMP pathway. Interference with the expression of G1 cyclins (in particular cyclin D3) by the antisense methodology strongly reduced TSH-dependent proliferation of PC Cl 3 cells, indicating that proper progression through G1 requires cyclin D3. Accordingly, PC Cl 3 cells engineered to overexpress cyclin D3 (PC-D3 cells) show enhanced growth rate and elude hormone-dependence and contact inhibition. Using an animal experimental model of thyroid stimulation, we demonstrate that cyclin D3 is a key mediator of TSH-dependent proliferation of thyroid follicular cells also in vivo. Cyclin D3 protein levels were higher in the thyrocytes from glands of propylthiouraciltreated rats compared with control animals. The increase in cyclin D3 expression occurred after the propylthiouracil-induced increase in TSH levels and preceded the burst of cell proliferation. Finally, we found that cyclin D3 protein is expressed in a fraction of human goiters but it is strongly overexpressed in most follicular adenomas.

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“…The sections were counterstained with hematoxylin, and then scanned at low power to identify areas that were evenly stained. Estimates of the numbers of positive cells were scored as follows: negative, 0%; 1, 1-10%; 2, 11-25%; 3, 26-50%; 4, >50% positive (Saiz et al 2002). Two independent investigators performed the estimation.…”

Section: Immunohistochemical Analysismentioning

confidence: 99%

Comprehensive gene expression profiling of anaplastic thyroid cancers with cDNA microarray of 25 344 genes

Onda¹,

Emi²,

Yoshida³

et al. 2004

Endocr Relat Cancer

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Little is known about the genetic mechanisms of anaplastic thyroid cancer (ATC). This is the most virulent of all human malignancies, and it is believed to result from transformation of differentiated thyroid cancers. To identify a set of genes involved in the development of ATC, we investigated expression profiles of 11 cell lines derived from ATC using a cDNA microarray representing 25 344 genes. Semi-quantitative RT-PCR experiments carried out for some genes that had shown altered expression on the microarray verified frequent over-expression of destrin, HSPA8, stathmin, LDH-A, ATP5A1, PSMB6, B23, HDP-1 and LDH-B, and frequent under-expression of thyroglobulin, PBP and c-FES/FPS genes among the cell lines and also among ten primary ATCs. In addition to mRNA expression studies, up-regulation of GDI2, destrin and stathmin were confirmed with immunohistochemical analysis. The extensive list of genes identified provides valuable information towards understanding the development of ATC, and provides a source of possible biomarkers for diagnosis and/or molecular targets for the development of novel drugs to treat ATC.

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Immunohistochemical expression of cyclin D1, E2F‐1, and Ki‐67 in benign and malignant thyroid lesions

Cited by 81 publications

References 20 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

Critical role of cyclin D3 in TSH-dependent growth of thyrocytes and in hyperproliferative diseases of the thyroid gland

Comprehensive gene expression profiling of anaplastic thyroid cancers with cDNA microarray of 25 344 genes

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