Dipartimento di Biologia e Patologia Cellulare e Molecolare/Istituto di Endocrinologia ed Oncologia Sperimentale del CNR G. Salvatore, Naples, Italy.
Cancer Res. 2011 Mar 1;71(5):1792-804. doi: 10.1158/0008-5472.CAN-10-2186. Epub 2011 Feb 22.
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.
甲状腺癌是最常见的内分泌癌，但关键的致癌驱动因素仍未确定。在这项研究中，我们发现趋化因子 CXCL12/SDF-1 可诱导表达 CXCR4 的甲状腺癌细胞中转录激活 TYRO3 和 AXL 受体酪氨酸激酶。这两种受体在甲状腺癌细胞系中持续表达，但在正常甲状腺细胞中不表达。由于其配体 GAS6 的组成性表达，AXL 在大多数癌细胞系中表现出高水平的酪氨酸磷酸化。在人类甲状腺癌标本中，但在正常甲状腺组织中，AXL 和 GAS6 常同时表达。在同时表达两种受体和配体的细胞系中，阻断每种受体或配体都显著影响细胞活力，并降低对凋亡刺激的抵抗力。用 GAS6 刺激缺乏 GAS6 的癌细胞会增加其增殖和存活。同样，siRNA 介导的 AXL 沉默抑制了裸鼠中甲状腺癌细胞的活力、侵袭性和肿瘤异种移植物的生长。我们的研究结果表明，TYRO3/AXL-GAS6 自分泌环维持甲状腺癌细胞的恶性特征，靶向该环可能为这种癌症提供一种新的治疗方法。
