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K Krause, Department of Internal Medicine, University of Leipzig, Leipzig, D-04103, Germany
S Karger, Department of Internal Medicine, University of Leipzig, Leipzig, Germany
S Sheu, Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany
T Aigner, Institute of Pathology, University of Leipzig, leipzig, Germany
R Kursawe, Department of Internal Medicine, University of Leipzig, Leipzig, Germany
O Gimm, Department of Surgery, University of Halle, Halle, Germany
K Schmid, Institute of Pathology and Neuropathology, University of Duisburg-Essen, Essen, Germany
H Dralle, Department of Surgery, University of Halle, Halle, Germany
D Fuhrer, Department of Internal Medicine, University of Leipzig, Leipzig, Germany

Correspondence: Kerstin Krause, Email: kerstin.krause{at}medizin.uni-leipzig.de

Abstract

We recently found an increased expression of APP in cold thyroid nodules, which are difficult to classify as a truly benign thyroid neoplasm or a lesion with the potential for further dedifferentiation. Since differences in APP activity have been found in other human cancers, we asked whether thyroid carcinogenesis might be associated with an altered APP expression and function. APP regulation was studied in vitro in differentiated (FRTL-5) and dedifferentiated (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the PKC cascades. In-vivo analysis of APP expression and downstream signalling was performed in benign and malignant thyroid tissues. We found that upregulation of APP expression and sAPP secretion is induced by TSH in differentiated thyroid cells and by insulin in thyroid cancer cells. PKC is a strong activator of APP cleavage and in FTC-133 confers prolonged release of the APP ectodomain. FTC-133 but not FRTL-5 cells show a prominent cell surface expression of the APP ectodomain, which has been suggested to function as an autocrine growth factor. Thyroid cancers are characterised by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.

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