Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene
Induction of a proinflammatory program in normal human thyrocytes by the RET/PTC1 oncogene
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DOI：
10.1073/pnas.0503039102
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发表时间：
2005-10-11
影响因子：
11.1
通讯作者：
Pierotti, MA
中科院分区：
文献类型：
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作者：
Borrello, MG;Alberti, L;Pierotti, MA
RET受体酪氨酸激酶基因重排产生RET/PTC癌基因是甲状腺乳头状癌（PTC）所特有的，甲状腺乳头状癌是最常见的甲状腺肿瘤。在此，我们表明，当RET/PTC1癌基因在原代正常人甲状腺细胞中外源表达时，会诱导大量参与炎症和肿瘤侵袭的基因表达，包括编码趋化因子（CCL2、CCL20、CXCL8和CXCL12）、趋化因子受体（CXCR4）、细胞因子（IL1B、CSF - 1、GM - CSF和G - CSF）、基质降解酶（金属蛋白酶和尿激酶型纤溶酶原激活物及其受体）以及黏附分子（L - 选择素）的基因。这种作用严格依赖于RET/PTC1的Tyr - 451（对应于RET的Tyr - 1062多对接位点）的存在。与正常甲状腺组织或甲状腺滤泡状癌相比，在甲状腺乳头状癌的临床样本中，特别是那些以RET/PTC激活、局部甲状腺外扩散和淋巴结转移为特征的样本中，发现选定的相关基因（CCL20、CCL2、CXCL8、CXCR4、L - 选择素、GM - CSF、IL1B、MMP9、UPA和SPP1/OPN）也上调。这些结果表明RET/PTC1癌基因激活了一个促炎程序，在一种转化的人类癌基因、炎症和恶性行为之间提供了直接联系。
Rearrangements of the RET receptor tyrosine kinase gene generating RET/PTC oncogenes are specific to papillary thyroid carcinoma (PTC), the most frequent thyroid tumor. Here, we show that the RET/PTC1 oncogene, when exogenously expressed in primary normal human thyrocytes, induces the expression of a large set of genes involved in inflammation and tumor invasion, including those encoding chemokines (CCL2, CCL20, CXCL8, and CXCL12), chemokine receptors (CXCR4), cytokines (IL1B, CSF-1, GM-CSF, and G-CSF), matrix-degrading enzymes (metalloproteases and urokinase-type plasminogen activator and its receptor), and adhesion molecules (L-selectin). This effect is strictly dependent on the presence of the RET/PTC1 Tyr-451 (corresponding to RET Tyr-1062 multidocking site). Selected relevant genes (CCL20, CCL2, CXCL8, CXCR4, L-selectin, GM-CSF, IL1B, MMP9, UPA, and SPP1/OPN) were found up-regulated also in clinical samples of IPTC, particularly those characterized by RET/PTC activation, local extrathyroid spread, and lymph node metastases, when compared with normal thyroid tissue or follicular thyroid carcinoma. These results, demonstrating that the RET/PTC1 oncogene activates a proinflammatory program, provide a direct link between a transforming human oncogene, inflammation, and malignant behavior.