SFEBES2009 Oral Communications Steroids and thyroid (8 abstracts)
Akt activation in a murine thyroid goitre model induced by the tumourigenic factor PBF
Martin Read 1 , Greg Lewy 1 , Neil Sharma 1 , Jim Fong 1 , Vicki Smith 1 , Robert Seed 1 , Perkin Kwan 1 , Wendy Leadbeater 1 , Adrian Warfield 2 , John Watkinson 2 , Jayne Franklyn 1 , Kristien Boelaert 1 & Chris McCabe 1
1University of Birmingham, Birmingham, West Midlands, UK; 2UHB NHS Foundation Trust, Birmingham, West Midlands, UK.
PTTG binding factor (PBF) is a poorly characterised transforming gene that is overexpressed in thyroid tumours and inhibits the activity of the sodium iodide symporter (NIS) in vitro. Our recent investigations demonstrated that PBF mRNA expression was 2.6-fold higher in thyroid tissue excised from patients with multinodular goitres (MNG) than in normal thyroid tissue (n=25, P<0.01). We have now generated a murine transgenic model of targeted overexpression of PBF in the thyroid to investigate its function in vivo. Thyroid glands of transgenic PBF mice were markedly enlarged with a mean weight of 6.0±1.1 mg (n=16) at 6 months of age compared to 2.95±0.5 mg (n=11, P<0.0001) in wild-type (WT) mice. By 12 months of age the mean weight of thyroids harvested from PBF mice had increased further to 10.6±2.7 mg (n=11). Histological examination showed that the percentage of large follicles was significantly greater (20 vs 7% follicles>100 μm in diameter, P<0.0001) in PBF mice compared to age-matched WT mice. Real-time RT-PCR analysis showed a significant twofold reduction in NIS mRNA levels (0.52±0.061, n=7, P<0.0001) in transgenic thyroids. There was no difference in thyroid function tests (serum T4 (3.1±0.9 vs 3.2±0.5 μg/dl, P=0.207), T3 (118.4±23.6 vs 140.5±17.2 ng/dl, P=0.128), and TSH (81.3±20.3 vs 74.7±14.7 ng/ml, P=0.669)) between PBF and WT mice, respectively, which suggested that altered thyroid function was not responsible for inducing goitrogenesis. Interestingly, there was no significant increase in mRNAs encoding growth factors known to induce thyroid cell proliferation including FGF2, EGF, VEGF, IGF1 and TGFβ. Western blot analysis however showed significant activation of the serine/threonine kinase Akt in transgenic thyroids, a known regulator of thyroid cancer cell proliferation. These results demonstrate that PBF is overexpressed in MNG and that targeted overexpression of PBF causes significant enlargement of the thyroid gland independent of thyroid function. Further, these results implicate Akt in mediating PBF-induced thyroid cell proliferation in vivo.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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