Oncogenic BRAF-Mediated Melanoma Cell Invasion.
Oncogenic BRAF-Mediated Melanoma Cell Invasion.
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DOI：
10.1016/j.celrep.2016.04.073
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发表时间：
2016-05-31
期刊：
影响因子：
8.8
通讯作者：
Guo W
中科院分区：
文献类型：
--
作者：
Lu H;Liu S;Zhang G;Kwong LN;Zhu Y;Miller JP;Hu Y;Zhong W;Zeng J;Wu L;Krepler C;Sproesser K;Xiao M;Xu W;Karakousis GC;Schuchter LM;Field J;Zhang PJ;Herlyn M;Xu X;Guo W
具有致癌BRAFV 600 E突变的黑色素瘤患者具有较差的预后。虽然BRAFV 600 E在肿瘤发生中的作用已经得到充分证实，但其在黑素瘤患者中临床观察到的侵袭中的参与仍然是一个争论的话题。在这里，我们表明，BRAFV 600 E黑色素瘤细胞具有广泛的侵袭活性，测定细胞外基质的降解，并产生F-肌动蛋白和corneumen灶，介导膜突起。BRAFV 600 E的抑制阻断黑素瘤细胞侵袭。在BRAFV 600 E驱动的鼠黑色素瘤模型中或在患者的肿瘤活检中，抑制剂治疗后皮质蛋白病灶减少。此外，全基因组表达分析显示，BRAFV 600 E抑制后，许多侵袭足相关基因下调。在机制上，BRAFV 600 E通过ERK诱导coronin和外囊亚基Exo 70的磷酸化，其分别调节肌动蛋白动力学和基质金属蛋白酶分泌。我们的研究结果为BRAFV 600 E在转移中的作用提供了支持，并表明抑制侵袭是一种潜在的抗黑色素瘤治疗策略。
Melanoma patients with oncogenic BRAFV600E mutation have poor prognoses. While the role of BRAFV600E in tumorigenesis is well established, its involvement in invasion that is clinically observed in melanoma patients, remains a topic of debate. Here we show that BRAFV600E melanoma cells have extensive invasion activity as assayed by degradation of extracellular matrix, and generation of F-actin and cortactin foci that mediate membrane protrusion. Inhibition of BRAFV600E blocks melanoma cell invasion. In a BRAFV600E-driven murine melanoma model or in patients’ tumor biopsies, cortactin foci decrease upon inhibitor treatment. In addition, genome-wide expression analysis shows that a number of invadopodia-related genes are down-regulated after BRAFV600E inhibition. Mechanistically, BRAFV600E induces phosphorylation of cortactin and the exocyst subunit Exo70 through ERK, which regulates actin dynamics and matrix metalloprotease secretion, respectively. Our results provide support for the role of BRAFV600E in metastasis, and suggest that inhibiting invasion is a potential therapeutic strategy against melanoma.