Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis
Pleckstrin homology domain-interacting protein (PHIP) as a marker and mediator of melanoma metastasis
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DOI：
10.1073/pnas.1119949109
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发表时间：
2012-05-01
影响因子：
11.1
通讯作者：
Kashani-Sabet, Mohammed
中科院分区：
文献类型：
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作者：
De Semir, David;Nosrati, Mehdi;Kashani-Sabet, Mohammed
虽然突变型v-Raf小鼠肉瘤病毒癌基因同源物B1（BRAF）的黑色素瘤现在可以有效地靶向，有没有大多数表达野生型BRAF的黑色素瘤的分子靶点。在这里，我们表明，Pleckstrin同源结构域相互作用蛋白（PHIP）的激活，促进黑色素瘤转移，可用于分类原发性黑色素瘤的一个子集，是黑色素瘤的预后生物标志物。基于质粒的靶向Phip的系统性shRNA抑制了黑色素瘤的转移进展，而在黑色素瘤细胞系中稳定抑制Phip抑制了转移潜力并延长了荷瘤小鼠的生存期。人PHIP基因位于6q14.1上，尽管在黑色素瘤中观察到6 q缺失，但PHIP基因座在黑色素瘤细胞系和患者样本中保留，其过表达是黑色素瘤患者生存的独立不良预测因子。此外，高比例的PHIP过表达黑色素瘤具有增加的PHIP拷贝数。PHIP过表达的黑色素瘤包括具有野生型BRAF、成神经细胞瘤RAS病毒（v-ras）癌基因同源物以及磷酸酶和张力蛋白同源物的肿瘤，证明了PHIP在三阴性黑色素瘤中的活化。这些结果描述了以前未报道的作用，PHIP在预测和促进黑色素瘤转移，并在黑色素瘤的分子分类。
Although melanomas with mutant v-Raf murine sarcoma viral oncogene homolog B1 (BRAF) can now be effectively targeted, there is no molecular target for most melanomas expressing wildtype BRAF. Here, we show that the activation of Pleckstrin homology domain-interacting protein (PHIP), promotes melanoma metastasis, can be used to classify a subset of primary melanomas, and is a prognostic biomarker for melanoma. Systemic, plasmid-based shRNA targeting of Phip inhibited the metastatic progression of melanoma, whereas stable suppression of Phip in melanoma cell lines suppressed metastatic potential and prolonged the survival of tumor-bearing mice. The human PHIP gene resides on 6q14.1, and although 6q loss has been observed in melanoma, the PHIP locus was preserved in melanoma cell lines and patient samples, and its overexpression was an independent adverse predictor of survival in melanoma patients. In addition, a high proportion of PHIP-overexpressing melanomas harbored increased PHIP copy number. PHIP-overexpressing melanomas include tumors with wild-type BRAF, neuroblastoma RAS viral (v-ras) oncogene homolog, and phosphatase and tensin homolog, demonstrating PHIP activation in triple-negative melanoma. These results describe previously unreported roles for PHIP in predicting and promoting melanoma metastasis, and in the molecular classification of melanoma.