Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer.
Granulin, a novel STAT3-interacting protein, enhances STAT3 transcriptional function and correlates with poorer prognosis in breast cancer.
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颗粒蛋白是一种新型的STAT3相互作用蛋白，可增强STAT3转录功能，并与乳腺癌的预后较差相关。
DOI：
10.18632/genesandcancer.58
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发表时间：
2015-03
期刊：
影响因子：
--
通讯作者：
Frank DA
中科院分区：
文献类型：
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作者：
Yeh JE;Kreimer S;Walker SR;Emori MM;Krystal H;Richardson A;Ivanov AR;Frank DA
由于细胞的肿瘤表型主要由异常基因表达模式驱动，因此越来越多的注意力集中在调节肿瘤发生的关键介质的转录因子，如信号转导子和转录激活子3（STAT3）。由于与STAT3相互作用的蛋白质可能是解决STAT3如何促进癌症发病机制的关键，因此我们采用蛋白质组学方法来鉴定新型STAT3相互作用蛋白。我们对来自乳腺癌细胞的含有STAT3的复合物进行了基于质谱的分析，这些乳腺癌细胞具有组成型活性STAT3，并且依赖于STAT3的生存功能。我们确定颗粒蛋白（GRN）作为一种新的STAT3相互作用的蛋白质，是必要的组成和最大白血病抑制因子（LIF）诱导的STAT3转录活性。GRN增强了乳腺癌细胞中STAT3 DNA结合，也增加了LIF诱导的STAT3活化的时间积分量。此外，沉默GRN中和了STAT3介导的致瘤表型，包括活力、克隆形成和迁移能力。在原发性乳腺癌样本中，GRN mRNA水平与STAT3基因表达特征呈正相关，并与患者生存率降低呈正相关。这些研究将GRN确定为功能上重要的STAT3相互作用蛋白，其可作为乳腺癌的重要预后生物标志物和潜在治疗靶点。
Since the neoplastic phenotype of a cell is largely driven by aberrant gene expression patterns, increasing attention has been focused on transcription factors that regulate critical mediators of tumorigenesis such as signal transducer and activator of transcription 3 (STAT3). As proteins that interact with STAT3 may be key in addressing how STAT3 contributes to cancer pathogenesis, we took a proteomics approach to identify novel STAT3-interacting proteins. We performed mass spectrometry-based profiling of STAT3-containing complexes from breast cancer cells that have constitutively active STAT3 and are dependent on STAT3 function for survival. We identified granulin (GRN) as a novel STAT3-interacting protein that was necessary for both constitutive and maximal leukemia inhibitory factor (LIF)induced STAT3 transcriptional activity. GRN enhanced STAT3 DNA binding and also increased the time-integrated amount of LIF-induced STAT3 activation in breast cancer cells. Furthermore, silencing GRN neutralized STAT3-mediated tumorigenic phenotypes including viability, clonogenesis, and migratory capacity. In primary breast cancer samples, GRN mRNA levels were positively correlated with STAT3 gene expression signatures and with reduced patient survival. These studies identify GRN as a functionally important STAT3-interacting protein that may serve as an important prognostic biomarker and potential therapeutic target in breast cancer.