TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition
TFE3 fusions activate MET signaling by transcriptional up-regulation, defining another class of tumors as candidates for therapeutic MET inhibition
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DOI：
10.1158/0008-5472.can-06-2855
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发表时间：
2007-02-01
期刊：
影响因子：
11.2
通讯作者：
Ladanyi, Marc
中科院分区：
文献类型：
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作者：
Tsuda, Masumi;Davis, Ian J.;Ladanyi, Marc
编码嵌合转录因子的特异性染色体易位被认为在多种人类癌症中发挥关键的致癌作用，但融合蛋白本身很少代表合适的治疗靶点。致瘤性TFE 3融合蛋白定义了儿科肾腺癌的一个子集，并且一种融合（ASPL-TFE 3）也是腺泡状软组织肉瘤（ASPS）的特征。通过表达谱分析，我们发现MET受体酪氨酸激酶基因在ASPS中相对于其他四种原始肉瘤显著过表达。因此，我们研究了MET作为ASPL= TFE 3的直接转录靶标。ASPL TFE 3与MET启动子结合并强烈激活它。同样，PSF-TFE 3和NONO= TFE 3也与该启动子结合。ASPL-TFE 3对MET的诱导导致在肝细胞生长因子（HGF）存在下强烈的MET自磷酸化和下游信号传导的激活。在含有内源性TFE 3融合蛋白的癌细胞系中，通过BNA干扰或通过抑制剂PHA 665752抑制MET可消除HGF依赖性MET活化，导致细胞生长减少和HGF依赖性表型丧失。因此，MET是这些癌症的潜在治疗靶点。致癌TFE 3融合蛋白对MET的异常转录上调代表了某些癌症依赖于MET信号传导的另一种机制。识别由致癌融合蛋白转录上调的激酶信号通路可能揭示这类人类癌症中更容易获得的治疗靶点。
Specific chromosomal translocations encoding chimeric transcription factors are considered to play crucial oncogenic roles in a variety of human cancers but the fusion proteins themselves seldom represent suitable therapeutic targets. Oncogenic TFE3 fusion proteins define a subset of pediatric renal adenocarcinomas and one fusion (ASPL-TFE3) is also characteristic of alveolar soft part sarcoma (ASPS). By expression profiling, we identified the MET receptor tyrosine kinase gene as significantly overexpressed in ASPS relative to four other types of primitive sarcomas. We therefore examined MET as a direct transcriptional target of ASPL=TFE3. ASPL TFE3 binds to the MET promoter and strongly activates it. Likewise, PSF-TFE3 and NONO=TFE3 also bind this promoter. Induction of MET by ASPL-TFE3 results in strong MET autophosphorylation and activation of downstream signaling in the presence of hepatocyte growth factor (HGF). In cancer cell lines containing endogenous TFE3 fusion proteins, inhibiting MET by BNA interference or by the inhibitor PHA665752 abolishes HGF-dependent MET activation, causing decreased cell growth and loss of HGF-dependent phenotypes. MET is thus a potential therapeutic target in these cancers. Aberrant transcriptional up-regulation of MET by oncogenic TFE3 fusion proteins represents another mechanism by which certain cancers become dependent on MET signaling. The identification of kinase signaling pathways transcriptionally up-regulated by oncogenic fusion proteins may reveal more accessible therapeutic targets in this class of human cancers.