Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis
Evidence for a role of the amyloid precursor protein in thyroid carcinogenesis
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DOI：
10.1677/joe-08-0005
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发表时间：
2008-08-01
影响因子：
4
通讯作者：
Fuhrer, Dagmar
中科院分区：
文献类型：
--
作者：
Krause, Kerstin;Karger, Stefan;Fuhrer, Dagmar
我们最近发现，在冷甲状腺结节中淀粉样前体蛋白（APP）的表达增加，这些结节很难归类为真正的良性甲状腺肿瘤或具有进一步去分化潜力的病变。因为在其他癌症中发现了APP活性的差异。我们想知道甲状腺癌的发生是否与APP表达和功能的改变有关。在特异性抑制或激活cAMP-PKA、PI 3 K/AKT或蛋白激酶c（PKC）级联后，在分化（FRTL-5）和去分化滤泡性甲状腺癌（FTC-133）甲状腺细胞中研究了APP调节。在良性和恶性甲状腺组织中进行APP表达和下游信号传导的体内分析。我们发现，APP的表达和SAPP分泌的上调诱导分化的甲状腺细胞中的TSH和甲状腺癌细胞中的胰岛素。PKC是APP切割的强激活剂，在FTC-133中可延长APP胞外域的释放。FTC-133而非FRTL-5-细胞显示APP胞外域的显著细胞表面表达，其已被认为作为所有自分泌生长因子起作用。甲状腺癌的特征在于APP上调、APP胞外域的膜靶向增加以及APP支架蛋白JIP 1、ShcA和Fe 65的mRNA水平显著增加。
We have recently found all 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 cancers. we asked whether thyroid carcinogenesis might be associated with all 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 downstrearn 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 all 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.