抑制黑色素瘤转移的新型疗法

近日，刊登在国际杂志Cancer Research上的一篇研究报告中，来自弗吉尼亚联邦大学癌症中心等处的研究者在实验条件下，通过抑制一种名为黑色素瘤分化相关基因-9（mad-9）/同线蛋白（syntenin），从而成功地抑制了黑色素瘤的转移。在美国每年有超过100万人被诊断为皮肤癌，这项研究为开发新型黑色素瘤的疗法提供了帮助。

在这项研究中，研究者发现Raf激酶蛋白（RKIP）可以和mad-9/同线蛋白进行作用并且抑制其表达，在此前研究中，研究者发现mad-9/同线蛋白可以和c-Src蛋白进行反应，进而发生一系列下游生化反应从而引发增加黑色素瘤发病风险。

研究者Fisher表示，前期研究揭示了RKIP在抑制黑色素瘤上扮演着重要角色，但是截止到现在，这种机制并不清楚，尽管我们发现了RKIP可以结合至mad-9/同线蛋白上，并且抑制其表达，这项研究就为开发类似于RKIP的小分子物质，用来治疗黑色素瘤的转移或者其它癌症的转移提供希望。

另外研究者发现，在恶性和转移性的黑色素瘤细胞中，mad-9/同线蛋白的水平比RKIP的水平要高，而在正常的黑色素细胞中，mad-9/同线蛋白的水平应该比RKIP低。这项研究为理解引发黑色素瘤的转移相关的遗传分子机制提供了帮助，也为开发新型的疗法提供了希望。（生物谷Bioon.com）

编译自：Research Breakthrough Could Halt Melanoma Metastasis, Study Suggests

doi:10.1158/0008-5472.CAN-12-0402
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Raf kinase inhibitor RKIP inhibits MDA-9/syntenin-mediated metastasis in melanoma

Swadesh K Das1, Sujit k Bhutia2, Upneet K Sokhi3, Belal Azab2, Zao-zhong Su1, Habib Boukerche4, Talha Anwar5, Erika L Moen5, Devasis Chatterjee6, Maurizio Pellecchia7, Devanand Sarkar8, and Paul B Fisher2,*

Melanoma differentiation associated gene-9 (MDA-9), also known as syntenin, functions as a positive regulator of melanoma progression and metastasis. In contrast, the Raf kinase inhibitor RKIP, a negative modulator of RAF-stimulated MEKK activation, is strongly downregulated in metastatic melanoma cells. In this study, we explored an hypothesized inverse relationship between MDA-9 and RKIP in melanoma. Tumor array and cell line analyses confirmed an inverse relationship between expression of MDA-9 and RKIP during melanoma progression. We found that MDA-9 transcriptionally downregulated RKIP in support of a suggested crosstalk between these two proteins. Further, MDA-9 and RKIP physically interacted in a manner that correlated with a suppression of FAK and c-Src phosphorylation, crucial steps necessary for MDA-9 to promote FAK/c-Src complex formation and initiate signaling cascades that drive the MDA-9-mediated metastatic phenotype. Lastly, ectopic RKIP expression in melanoma cells overrode MDA-9-mediated signaling, inhibiting cell invasion, anchorage-independent growth and in vivo dissemination of tumor cells. Taken together, these findings establish RKIP as an inhibitor of MDA-9-dependent melanoma metastasis, with potential implications for targeting this process therapeutically.