Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer
Activation of TYRO3/AXL Tyrosine Kinase Receptors in Thyroid Cancer
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DOI：
10.1158/0008-5472.can-10-2186
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发表时间：
2011-03-01
期刊：
影响因子：
11.2
通讯作者：
Melillo, Rosa Marina
中科院分区：
文献类型：
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作者：
Avilla, Elvira;Guarino, Valentina;Melillo, Rosa Marina
甲状腺癌是最常见的内分泌癌，但其关键致癌驱动因素仍不明确。在这项研究中，我们确定了TYRO 3和AXL受体酪氨酸激酶作为趋化因子CXCL 12/SDF-1在CXCR 4表达的甲状腺癌细胞中的转录靶点。这两种受体在甲状腺癌细胞系中组成型表达，但在正常甲状腺细胞中不表达。由于其配体GAS 6的组成性表达，AXL在大多数癌细胞系中显示高水平的酪氨酸磷酸化。在甲状腺癌组织中，AXL和GAS 6常呈共表达，而在正常甲状腺组织中则无。在同时表达受体和配体的细胞系中，阻断每个受体或配体显著影响细胞活力并降低对凋亡刺激的抗性。用GAS 6刺激GAS 6阴性癌细胞增加了它们的增殖和存活。类似地，siRNA介导的AXL沉默抑制癌细胞活力、侵袭力和裸鼠中肿瘤异种移植物的生长。我们的研究结果表明，TYRO 3/AXL-GAS 6自分泌回路维持了甲状腺癌细胞的恶性特征，靶向该回路可以为这种癌症提供一种新的治疗方法。Cancer Res; 71（5）; 1792-804. (c)2011年AACR。
Thyroid cancer is the most common endocrine cancer, but its key oncogenic drivers remain undefined. In this study we identified the TYRO3 and AXL receptor tyrosine kinases as transcriptional targets of the chemokine CXCL12/SDF-1 in CXCR4-expressing thyroid cancer cells. Both receptors were constitutively expressed in thyroid cancer cell lines but not normal thyroid cells. AXL displayed high levels of tyrosine phosphorylation in most cancer cell lines due to constitutive expression of its ligand GAS6. In human thyroid carcinoma specimens, but not in normal thyroid tissues, AXL and GAS6 were often coexpressed. In cell lines expressing both receptors and ligand, blocking each receptor or ligand dramatically affected cell viability and decreased resistance to apoptotic stimuli. Stimulation of GAS6-negative cancer cells with GAS6 increased their proliferation and survival. Similarly, siRNA-mediated silencing of AXL inhibited cancer cell viability, invasiveness, and growth of tumor xenografts in nude mice. Our findings suggest that a TYRO3/AXL-GAS6 autocrine circuit sustains the malignant features of thyroid cancer cells and that targeting the circuit could offer a novel therapeutic approach in this cancer. Cancer Res; 71(5); 1792-804. (c) 2011 AACR.