Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis.
We have recently found an increased expression of amyloid precursor protein (APP) in cold thyroid nodules that 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 follicular thyroid carcinomas (FTC-133) thyroid cells after specific inhibition or activation of the cAMP-PKA, the PI3K/AKT or the protein kinase c (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 characterized by APP upregulation, increased membrane targeting of the APP ectodomain and significantly increased mRNA levels of the APP scaffold proteins JIP1, ShcA and Fe65.
Krause
Kerstin
K
Division of Endocrinology, Department of Internal Medicine, University of Leipzig, Ph.-Rosenthal-Str. 27, D-04103 Leipzig, Germany.
Karger
Stefan
S
Sheu
Sien-Yi
SY
Aigner
Thomas
T
Kursawe
Romy
R
Gimm
Oliver
O
Schmid
Kurt-Werner
KW
Dralle
Henning
H
Fuhrer
Dagmar
D
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D016564:Amyloid beta-Protein Precursor / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007328:Insulin / Q000494:pharmacology; D018613:Microscopy, Confocal; D009419:Nerve Tissue Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D021381:Protein Transport / Q000187:drug effects; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055765:Shc Signaling Adaptor Proteins / Q000235:genetics; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013961:Thyroid Gland / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013964:Thyroid Neoplasms / Q000209:etiology / Q000378:metabolism* / Q000473:pathology; D013972:Thyrotropin / Q000494:pharmacology
C091042:APBB1 protein, human; D048868:Adaptor Proteins, Signal Transducing; D016564:Amyloid beta-Protein Precursor; D007328:Insulin; C490666:MAPK8IP1 protein, human; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C528024:SHC1 protein, human; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D013972:Thyrotropin