Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma
Active CREB1 Promotes a Malignant TGFβ2 Autocrine Loop in Glioblastoma
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DOI：
10.1158/2159-8290.cd-14-0275
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发表时间：
2014-10-01
期刊：
影响因子：
28.2
通讯作者：
Seoane, Joan
中科院分区：
文献类型：
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作者：
Rodon, Laura;Gonzalez-Junca, Alba;Seoane, Joan
在包括胶质母细胞瘤在内的晚期癌症中，TGF β通路是一种致癌因子。一些肿瘤表现出异常高的TGF - β活性，这一现象的机制尚不清楚。我们观察到TGF β可以诱导TGF β 2，产生一个自分泌循环，导致TGF β 2水平异常高。我们发现camp响应元件结合蛋白1 （CREB1）是TGF β诱导TGF β 2的关键介质。CREB1与SMAD3协同结合TGFB2基因启动子，是TGF β激活转录所必需的。此外，PI3K-AKT和RSK通路通过CREB1调节TGF β 2自分泌环。胶质母细胞瘤中CREB1和活性磷酸化CREB1的水平与TGF β 2相关。此外，通过患者来源的胶质母细胞瘤体内模型，我们发现CREB1水平决定TGF β 2的表达。我们的研究结果表明，CREB1可以被认为是一种生物标志物，用于对患者进行抗tgf β治疗和胶质母细胞瘤的治疗靶点。意义：TGF β被认为是一个很有前景的治疗靶点，一些使用TGF β抑制剂的临床试验正在产生令人鼓舞的结果。在这里，我们发现了在某些肿瘤中发现的异常高水平TGF β 2的分子机制，我们提出了生物标志物来预测抗TGF β治疗的临床反应。(c) 2014年aacr。
In advanced cancer, including glioblastoma, the TGF beta pathway acts as an oncogenic factor. Some tumors exhibit aberrantly high TGF beta activity, and the mechanisms underlying this phenomenon are not well understood. We have observed that TGF beta can induce TGF beta 2, generating an autocrine loop leading to aberrantly high levels of TGF beta 2. We identified cAMP-responsive element-binding protein 1 (CREB1) as the critical mediator of the induction of TGF beta 2 by TGF beta. CREB1 binds to the TGFB2 gene promoter in cooperation with SMAD3 and is required for TGF beta to activate transcription. Moreover, the PI3K-AKT and RSK pathways regulate the TGF beta 2 autocrine loop through CREB1. The levels of CREB1 and active phosphorylated CREB1 correlate with TGF beta 2 in glioblastoma. In addition, using patient-derived in vivo models of glioblastoma, we found that CREB1 levels determine the expression of TGF beta 2. Our results show that CREB1 can be considered a biomarker to stratify patients for anti-TGF beta treatments and a therapeutic target in glioblastoma.SIGNIFICANCE: TGF beta is considered a promising therapeutic target, and several clinical trials using TGF beta inhibitors are generating encouraging results. Here, we discerned the molecular mechanisms responsible for the aberrantly high levels of TGF beta 2 found in certain tumors, and we propose biomarkers to predict the clinical response to anti-TGF beta therapies. (C) 2014 AACR.