Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer.
Lysophosphatidic acid activates Arf6 to promote the mesenchymal malignancy of renal cancer.
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DOI：
10.1038/ncomms10656
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发表时间：
2016-02-08
影响因子：
16.6
通讯作者：
Sabe H
中科院分区：
文献类型：
--
作者：
Hashimoto S;Mikami S;Sugino H;Yoshikawa A;Hashimoto A;Onodera Y;Furukawa S;Handa H;Oikawa T;Okada Y;Oya M;Sabe H
癌细胞获得间充质特性是其恶性行为的关键，但对间充质分子机制及其如何激活的调节仍然难以捉摸。在这里，我们发现肾透明细胞癌(CcRCC)经常利用基于Arf6的间质途径来促进侵袭和转移，类似于乳腺癌。在乳腺癌细胞中，配体激活的受体酪氨酸激酶使用GEP100激活Arf6，Arf6然后招募AMAP1；AMAP1然后与间质特异性蛋白EPB41L5结合，促进上皮-间充质转化和局部黏附动力学。在肾癌细胞中，溶血磷脂酸(LPA)通过其G蛋白偶联受体激活Arf6，其中GTP-Gα12与EF6结合。基于Arf6的途径也可能与耐药有关。我们的结果表明，原发性肾小管细胞癌存在一种特殊的间质分子机制，这种机制由自体趋化蛋白的产物触发，与患者的不良预后有关。癌细胞间充质特性的获得是恶性肿瘤发生发展的关键事件。在此，作者发现，在肾癌细胞中，溶磷脂酸不利用RhoA途径，而是通过其GPCRs和EFA6特异性地激活Arf6间充质途径，促进侵袭、转移和耐药。
Acquisition of mesenchymal properties by cancer cells is critical for their malignant behaviour, but regulators of the mesenchymal molecular machinery and how it is activated remain elusive. Here we show that clear cell renal cell carcinomas (ccRCCs) frequently utilize the Arf6-based mesenchymal pathway to promote invasion and metastasis, similar to breast cancers. In breast cancer cells, ligand-activated receptor tyrosine kinases employ GEP100 to activate Arf6, which then recruits AMAP1; and AMAP1 then binds to the mesenchymal-specific protein EPB41L5, which promotes epithelial–mesenchymal transition and focal adhesion dynamics. In renal cancer cells, lysophosphatidic acid (LPA) activates Arf6 via its G-protein-coupled receptors, in which GTP-Gα12 binds to EFA6. The Arf6-based pathway may also contribute to drug resistance. Our results identify a specific mesenchymal molecular machinery of primary ccRCCs, which is triggered by a product of autotaxin and it is associated with poor outcome of patients. Acquisition of mesenchymal properties by cancer cells is a critical event for the development of malignancy. Here, the authors show that in renal cancer cells, lysosphosphatidic acid does not utilize the RhoA pathway but specifically activates the Arf6 mesenchymal pathway via its GPCRs and EFA6 to promote invasion, metastasis and drug resistance.