Key contribution of CPEB4-mediated translational control to cancer progression
Key contribution of CPEB4-mediated translational control to cancer progression
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DOI：
10.1038/nm.2540
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发表时间：
2012-01-01
期刊：
影响因子：
82.9
通讯作者：
Navarro, Pilar
中科院分区：
文献类型：
--
作者：
Ortiz-Zapater, Elena;Pineda, David;Navarro, Pilar
恶性转化、侵袭和血管生成依赖于肿瘤起源细胞中基因表达的协调重编程。尽管在基因组和表观遗传尺度上已经广泛地研究了去调控的基因表达，但是mRNA特异性翻译的调控对这种重编程的贡献还没有很好地理解。在这里，我们表明，细胞质多聚腺苷酸化元件结合蛋白4（CPEB 4），一种RNA结合蛋白，介导减数分裂mRNA细胞质多聚腺苷酸化和翻译，在胰腺导管腺癌和胶质母细胞瘤中过表达，在那里它支持肿瘤生长，血管形成和侵袭。我们还表明，在胰腺肿瘤中，CPEB 4的促癌功能起源于正常组织中沉默的mRNA的翻译激活，包括组织纤溶酶原激活物的mRNA，这是胰腺导管腺癌恶性肿瘤的关键因素。总之，我们的研究结果证明了转录后基因调控在肿瘤发展中的关键作用，并描述了恶性肿瘤进展相关的基因表达重编程的详细机制。
Malignant transformation, invasion and angiogenesis rely on the coordinated reprogramming of gene expression in the cells from which the tumor originated. Although deregulated gene expression has been extensively studied at genomic and epigenetic scales, the contribution of the regulation of mRNA-specific translation to this reprogramming is not well understood. Here we show that cytoplasmic polyadenylation element binding protein 4 (CPEB4), an RNA binding protein that mediates meiotic mRNA cytoplasmic polyadenylation and translation, is overexpressed in pancreatic ductal adenocarcinomas and glioblastomas, where it supports tumor growth, vascularization and invasion. We also show that, in pancreatic tumors, the pro-oncogenic functions of CPEB4 originate in the translational activation of mRNAs that are silenced in normal tissue, including the mRNA of tissue plasminogen activator, a key contributor to pancreatic ductal adenocarcinoma malignancy. Taken together, our results document a key role for post-transcriptional gene regulation in tumor development and describe a detailed mechanism for gene expression reprogramming underlying malignant tumor progression.