Global analysis of BRAFV600E target genes in human melanocytes identifies matrix metalloproteinase-1 as a critical mediator of melanoma growth.
Global analysis of BRAFV600E target genes in human melanocytes identifies matrix metalloproteinase-1 as a critical mediator of melanoma growth.
复制标题
对人类黑色素细胞中 BRAFV600E 靶基因的整体分析表明，基质金属蛋白酶-1 是黑色素瘤生长的关键介质。
DOI：
10.1038/jid.2011.65
复制
发表时间：
2011
期刊：
影响因子：
--
通讯作者：
Alani,RhodaM
中科院分区：
文献类型：
--
作者：
Ryu,Byungwoo;Moriarty,WheiF;Stine,MeganJ;DeLuca,Amena;Kim,DaveS;Meeker,AlanK;Grills,LandonD;Switzer,RebeccaA;Eller,MarkS;Alani,RhodaM
已发现BRAF激酶在多达70%的良性痣和黑色素瘤中被突变激活(Davies等人，2002年)。它已被认为是黑色素瘤发展的关键介质，V600E激活突变代表了色素痣和黑色素瘤中最常见的BRAF突变形式(Pollock等人，2003年)。尽管有强有力的证据表明BRAF激酶在黑色素瘤中是一种真正的癌基因，但到目前为止，它在黑素细胞中的确切下游靶点还没有被定义，而且在黑色素瘤中BRAF特异的基因签名仍然不确定(Hoek等人，2006年)。我们将激活的BRAFV600E引入人类原代黑素细胞(HPMS)，以评估其特定功能(图1a，也请参见补充信息以了解实验方法的详细信息)。将BRAFV600E的急性表达诱导的HPMS的基因表达特征与表达GFP的HPMS进行了比较(图1c)。完整的数据集可以作为GSE13827a访问。我们发现，HPMS的BRAFV600E特征是几个促进生长的基因以及细胞运动和炎症相关基因的上调(图1b)，具有共同的细胞生长/增殖和凋亡网络激活(图S1)。这
BRAF kinase has been found to be mutationally activated in up to 70% of benign nevi and melanomas (Davies et al., 2002). It has been implicated as a critical mediator of melanoma development, with the V600E activating mutation representing the most commonly mutated form of BRAF in nevi and melanomas (Pollock et al., 2003). Despite strong evidence implicating BRAF kinase as a bona-fide oncogene in melanoma, its precise downstream targets in melanocytes have not been defined to date, and a BRAF-specific gene signature in melanomas remains uncertain (Hoek et al., 2006).We have introduced activated BRAFV600E into human primary melanocytes (HPMs) in order to assess its specific functions (Figure 1a and also see the supplemental information for details of experimental methods). The gene expression signature of HPMs induced by acute expression of the BRAFV600E was assessed in comparison to HPMs expressing GFP (Figure 1c). The complete dataset is accessible as GSE13827a. We found that the BRAFV600E signature of HPMs was characterized by upregulation of several growth promoting genes and cellular motility and inflammation associated genes (Figure 1b) with a common network activation of cellular growth/proliferation and apoptosis (Figure S1). This