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Regulatory Effects of TGF-β Superfamily Members on Normal and Neoplastic Thyroid Epithelial Cells
Uppsala University, Medicinska vetenskapsområdet, Faculty of Medicine, Department of Genetics and Pathology.
2002 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Thyroid growth and function is partly regulated by growth factors binding to receptors on the cell surface. In the present thesis, the transforming growth factor-β (TGF-β) superfamily members have been studied for their role in regulation of growth and differentiation of both normal and neoplastic thyroid epithelial cells.

TGF-β1 is a negative regulator of thyrocyte growth and function. However, the importance of other TGF-β superfamily members has not been fully investigated. TGF-β1, activin A, bone morphogenetic protein (BMP)-7 and their receptors were found to be expressed in porcine thyrocytes. In addition to TGF-β1, activin A was also found to be a negative regulator of thyroid growth and function, and both stimulated phosphorylation and nuclear translocation of Smad proteins. Furthermore, TGF-β1 and epidermal growth factor (EGF) demonstrated a synergistic negative effect on thyrocyte differentiation. Simultaneous addition of the two factors resulted in a loss of the transepithelial resistance and expression of the epithelial marker E-cadherin. This was followed by a transient expression of N-cadherin.

Despite the extremely malignant character of anaplastic thyroid carcinoma (ATC) tumor cells, established cell lines are still responsive to TGF-β1. A majority of the cell lines were also found to be growth inhibited by BMP-7. BMP-7 induced cell cycle arrest of the ATC cell line HTh 74 in a dose- and cell density-dependent manner. This was associated with upregulation of p21CIP1 and p27KIP1, decreased cyclin-dependent kinase (Cdk) activity and hypophosphorylation of the retinoblastoma protein (pRb). TGF-β1, and to some extent also BMP-7, induced the expression of N-cadherin and matrix metalloproteinase (MMP)-2 and -9. Stimulation of HTh 74 cells with TGF-β1 increased the migration through a reconstituted basement membrane indicating an increased invasive phenotype of the cells.

Taken together, these data show that TGF-β superfamily members not only affect growth and function of normal thyroid follicle cells but may also, in combination with EGF, play a role in cell dedifferentiation. This study additionally suggests that the TGF-β superfamily members may be important for the invasive properties of ATC cells.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis , 2002. , p. 56
Series
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 0282-7476 ; 1114
Keywords [en]
Genetics, activin, BMP, cadherin, carcinoma, cell cycle arrest, dedifferentiation, EGF, growth inhibition, invasion, Smad, TGF-β, thyroid
Keywords [sv]
Genetik
National Category
Medical Genetics
Research subject
Pathology
Identifiers
URN: urn:nbn:se:uu:diva-1624ISBN: 91-554-5216-7 (print)OAI: oai:DiVA.org:uu-1624DiVA, id: diva2:161221
Public defence
2002-02-09, Rudbecksalen, Rudbecklaboratoriet, Uppsala, 09:15
Opponent
Available from: 2002-01-16 Created: 2002-01-16 Last updated: 2018-01-13Bibliographically approved
List of papers
1. Expression of transforming growth factor-β1, activin A and their receptors in thyroid follicle cells: negative regulation of thyroid growth and function
Open this publication in new window or tab >>Expression of transforming growth factor-β1, activin A and their receptors in thyroid follicle cells: negative regulation of thyroid growth and function
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1999 In: Endocrinology, Vol. 140, no 9, p. 4300-4310Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89592 (URN)
Available from: 2002-01-16 Created: 2002-01-16Bibliographically approved
2. Transforming growth factor-β1-induced loss of the thyroid epithelial phenotype requires epidermal growth factor receptor signalling through MEK activation
Open this publication in new window or tab >>Transforming growth factor-β1-induced loss of the thyroid epithelial phenotype requires epidermal growth factor receptor signalling through MEK activation
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-89593 (URN)
Available from: 2002-01-16 Created: 2002-01-16 Last updated: 2010-01-13Bibliographically approved
3. BMP-7-induced cell cycle arrest of anaplastic thyroid carcinoma cells via p21CIP1 and p27KIP1
Open this publication in new window or tab >>BMP-7-induced cell cycle arrest of anaplastic thyroid carcinoma cells via p21CIP1 and p27KIP1
2001 In: Biochem Biophys Res Commun, Vol. 285, no 3, p. 773-781Article in journal (Refereed) Published
Identifiers
urn:nbn:se:uu:diva-89594 (URN)
Available from: 2002-01-16 Created: 2002-01-16Bibliographically approved
4. TGF-β superfamily members increase the invasive phenotype of human anaplastic thyroid carcinoma cells
Open this publication in new window or tab >>TGF-β superfamily members increase the invasive phenotype of human anaplastic thyroid carcinoma cells
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Manuscript (Other academic)
Identifiers
urn:nbn:se:uu:diva-89595 (URN)
Available from: 2002-01-16 Created: 2002-01-16 Last updated: 2010-01-13Bibliographically approved

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