Gab2-Mediated Signaling Promotes Melanoma Metastasis
Gab2-Mediated Signaling Promotes Melanoma Metastasis
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DOI：
10.2353/ajpath.2009.080543
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发表时间：
2009-04-01
影响因子：
6
通讯作者：
Celebi, Julide Tok
中科院分区：
文献类型：
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作者：
Horst, Basil;Gruvberger-Saal, Sofia K.;Celebi, Julide Tok
转移性黑色素瘤是一种目前缺乏有效治疗的预后不良的疾病。转移的关键生物学特征包括获得迁移能力、生长因子独立性和侵袭潜力。在试图确定基因，有助于黑色素瘤的发病机制，全基因组搜索使用细菌人工染色体阵列比较基因组杂交和单核苷酸多态性阵列在一系列的64个转移性黑色素瘤样本和20个黑色素瘤细胞系确定增加拷贝数的Gab 2位于11q14.1。Gab 2是增强Ras-Erk和PI 3 K-Akt通路的活化的衔接蛋白，并且最近与人类癌症有关;然而，其在黑色素瘤中的作用尚未被探索。在这项研究中，我们发现Gab 2在黑色素瘤中扩增（类似于11%）和/或过表达（类似于50%）。Gab 2蛋白表达与临床黑色素瘤进展相关，并且与原发性黑色素瘤和黑色素细胞痣相比，在转移性黑色素瘤中观察到更高水平的表达。我们发现Gab 2的过度表达增强了黑色素瘤细胞的迁移和侵袭，而Gab 2的沉默减少了黑色素瘤细胞的迁移和侵袭。在生长因子不存在的情况下，Gab 2介导Akt信号的过度激活，而PI 3 K-Akt通路的抑制降低Gab 2介导的肿瘤细胞迁移和侵袭潜力。Gab 2过表达导致体内肿瘤生长和转移潜能增强。这些研究证明了Gab 2在黑色素瘤肿瘤进展和转移中以前未定义的作用。(Am J Pathol 2009，174：1524-1533; DOI：10.2353/ajpath.2009.080543）
Metastatic melanoma is a disease with a poor prognosis that currently lacks effective treatments. Critical biological features of metastasis include acquisition of migratory competence, growth factor independence, and invasive potential. In an attempt to identify genes that contribute to melanoma pathogenesis, a genome-wide search using bacterial artificial chromosome array comparative genomic hybridization and single nucleotide polymorphism arrays in a series of 64 metastatic melanoma samples and 20 melanoma cell lines identified increased copy numbers of Gab2 located on 11q14.1. Gab2 is an adaptor protein that potentiates the activation of the Ras-Erk and PI3K-Akt pathways and has recently been implicated in human cancer; however, its role in melanoma has not been explored. In this study, we found that Gab2 was either amplified (similar to 11%) and/or overexpressed (similar to 50%) in melanoma. Gab2 protein expression correlated with clinical melanoma progression, and higher levels of expression were seen in metastatic melanomas compared with primary melanoma and melanocytic nevi. We found that overexpression of Gab2 potentiates, whereas silencing of Gab2 reduces, migration and invasion of melanoma cells. Gab2 mediated the hyperactivation of Akt signaling in the absence of growth factors, whereas inhibition of the PI3K-Akt pathway decreased Gab2-mediated tumor cell migration and invasive potential. Gab2 overexpression resulted in enhanced tumor growth and metastatic potential in vivo. These studies demonstrate a previously undefined role for Gab2 in melanoma tumor progression and metastasis. (Am J Pathol 2009, 174:1524-1533; DOI: 10.2353/ajpath.2009.080543)