Mol Cancer Res：GAS6/Axl信号轴在前列腺癌转移中起关键作用

在多种癌症中受体酪氨酸激酶Axl都过度表达，Axl主要在肿瘤细胞的增殖和侵袭过程中发挥作用。

早期研究数据表明，Axl和其配体生长阻滞特异性因子-6（GAS6）可能在建立有利于肿瘤转移性休眠的骨髓微环境中发挥作用。目前刊登在Molecular Cancer Research杂志上的一则研究中，研究人员发现转移性前列腺癌细胞株PC3和DU145L中Axl是高表达的，低转移性癌细胞系LNCaP中Axl的表达水平是较低的。

敲除PC3和DU145细胞中Axl导致几大间质标志物包括Snail、Slug和N-钙粘蛋白的表达降低，而上皮标记物E-钙粘蛋白的表达上升，这表明Axl在前列腺上皮间质转化过程中发挥作用。

敲除PC3和DU145细胞中Axl后，肿瘤细胞的体外迁移和侵袭能力也降低。有趣的是，当用GAS6处理PC3和DU145细胞后，Axl蛋白水平是下降的。

此外使用氯化钴（缺氧诱导剂剂）能抑制这些细胞株GAS6介导Axl蛋白水平的下调。人类前列腺癌组织芯片免疫组化染色显示，与正常组织相比，Axl、GAS6和缺氧诱导因子-1α均表达在前列腺癌组织和骨转移组织中。

总之，研究表明Axl在前列腺癌转移中起着至关重要的作用，GAS6具有调节Axl表达的作用。

doi:10.1158/1541-7786.MCR-11-0569
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Hypoxia Stabilizes GAS6/Axl Signaling in Metastatic Prostate Cancer

Anjali Mishra, Jingcheng Wang, Yusuke Shiozawa, Samantha McGee, Jinkoo Kim, Younghun Jung, et al.

The receptor tyrosine kinase Axl is overexpressed in a variety of cancers and is known to play a role in proliferation and invasion. Previous data from our laboratory indicate that Axl and its ligand growth arrest–specific 6 (GAS6) may play a role in establishing metastatic dormancy in the bone marrow microenvironment. In the current study, we found that Axl is highly expressed in metastatic prostate cancer cell lines PC3 and DU145 and has negligible levels of expression in a nonmetastatic cancer cell line LNCaP. Knockdown of Axl in PC3 and DU145 cells resulted in decreased expression of several mesenchymal markers including Snail, Slug, and N-cadherin, and enhanced expression of the epithelial marker E-cadherin, suggesting that Axl is involved in the epithelial–mesenchymal transition in prostate cancer cells. The Axl-knockdown PC3 and DU145 cells also displayed decreased in vitro migration and invasion. Interestingly, when PC3 and DU145 cells were treated with GAS6, Axl protein levels were downregulated. Moreover, CoCl₂, a hypoxia mimicking agent, prevented GAS6-mediated downregulation of Axl in these cell lines. Immunochemical staining of human prostate cancer tissue microarrays showed that Axl, GAS6, and hypoxia-inducible factor-1α (Hif-1α; indicator of hypoxia) were all coexpressed in prostate cancer and in bone metastases compared with normal tissues. Together, our studies indicate that Axl plays a crucial role in prostate cancer metastasis and that GAS6 regulates the expression of Axl. Importantly, in a hypoxic tumor microenvironment Axl expression is maintained leading to enhanced signaling.