Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway
Ras-induced invasion and metastasis are regulated by a leukotriene B4 receptor BLT2-linked pathway
复制标题
DOI：
10.1038/onc.2009.412
复制
发表时间：
2010-02-25
期刊：
影响因子：
8
通讯作者：
Kim, J-H
中科院分区：
文献类型：
--
作者：
Kim, E-Y;Seo, J-M;Kim, J-H
Ras信号通路因其参与癌细胞增殖而得到广泛认可；然而，对于它们在侵袭和转移中的作用知之甚少。在这里，我们证明了一个新的BLT2，一个低亲和力的白三烯B-4受体连接的信号级联，涉及通过Nox1， nf - κ B刺激和随后的基质金属蛋白酶9 （MMP-9）的上调产生活性氧（ROS），是Ras促进侵袭和转移的潜在机制。我们发现抑制BLT2信号可以显著抑制ras诱发的转移，并降低小鼠的相关死亡率。与提出的BLT2作为Ras信号传导转移的关键下游介质的作用一致，BLT2单独表达可导致大量转移性肺结节的形成，并且通过抑制BLT2的下游成分MMP-9可显著减弱结节的形成。总之，我们的研究结果揭示了blt2相关级联在驱动癌性ras诱导转移中的先前未被怀疑的功能，并将为侵袭和转移提供有价值的见解。中华肿瘤杂志（2010）29,1167-1178；doi: 10.1038 / onc.2009.412;2009年11月23日在网上发表
Ras signaling pathways are well-recognized for their involvement in cancer cell proliferation; however, considerably less is known regarding their contribution to invasion and metastasis. Here, we demonstrate that a novel BLT2, a low-affinity leukotriene B-4 receptor-linked signaling cascade involving the generation of reactive oxygen species (ROS) via Nox1, NF-kappa B stimulation and subsequent upregulation of matrix metalloproteinase-9 (MMP-9) is a potential mechanism by which Ras promotes invasion and metastasis. We found that inhibition of BLT2 signaling markedly suppressed Ras-evoked metastasis and reduced the associated mortality in mice. Consistent with the proposed role of BLT2 as a key downstream mediator of Ras signaling to metastasis, BLT2 expression alone resulted in the formation of numerous metastatic lung nodules and the nodules formation was significantly attenuated by the inhibition of MMP-9, a downstream component of BLT2. Together, our results reveal the previously unsuspected function of BLT2-linked cascade in driving oncogenic Ras-induced metastasis and would provide a valuable insight into invasion and metastasis. Oncogene (2010) 29, 1167-1178; doi: 10.1038/onc.2009.412; published online 23 November 2009