Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis
Overexpression of the RNA binding protein HuR impairs tumor growth in triple negative breast cancer associated with deficient angiogenesis
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DOI：
10.4161/cc.9.16.12711
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发表时间：
2010-08-15
期刊：
影响因子：
4.3
通讯作者：
Atasoy, Ulus
中科院分区：
文献类型：
--
作者：
Gubin, Matthew M.;Calaluce, Robert;Atasoy, Ulus
RNA 结合蛋白 (RBP) 和基因之间的相互作用尚不清楚，尤其是在血管生成的调节方面。 RBP HuR 与不稳定 mRNA 的富含 AU (ARE) 区域结合，促进它们翻译成蛋白质，并被假设为肿瘤维持基因。细胞质 HuR 水平升高与许多癌症（包括乳腺癌）的侵袭性增加和预后不良直接相关。 HuR 控制参与血管生成的多个基因的表达，包括 VEGF α、HIF1 α 和血小板反应蛋白 1 (TSP1)。我们研究了 HuR 在雌激素受体阴性 (ER) 乳腺癌中的作用。 HuR 水平较高的 MDA-MB-231 细胞的细胞周期动力学发生改变，生长速度加快。出乎意料的是，HuR 过表达显着干扰原位小鼠模型中的肿瘤生长。假定的机制似乎是通过增加 TSP1 的表达来产生抗血管生成作用，但令人惊讶的是，下调 VEGF（HuR 通常增加的目标）。我们的研究结果表明，HuR 可能调节一组参与血管形成的基因，从而控制肿瘤血管生成。调节 HuR 水平的方法可以克服与针对肿瘤血管形成的单一疗法相关的局限性。
Interactions between RNA binding proteins (RBPs) and genes are not well understood, especially in regulation of angiogenesis. The RBP HuR binds to the AU-rich (ARE) regions of labile mRNAs, facilitating their translation into protein and has been hypothesized to be a tumor-maintenance gene. Elevated levels of cytoplasmic HuR directly correlate with increased invasiveness and poor prognosis for many cancers, including those of the breast. HuR controls the expression of multiple genes involved in angiogenesis including VEGF alpha, HIF1 alpha and thrombospondin 1 (TSP1). We investigated the role of HuR in estrogen receptor negative (ER) breast cancer. MDA-MB-231 cells with higher levels of HuR have alterations in cell cycle kinetics and faster growth. Unexpectedly, HuR overexpression significantly interfered with tumor growth in orthotopic mouse models. The putative mechanism seems to be an anti-angiogenetic effect by increasing expression of TSP1 but also surprisingly, downregulating of VEGF, a target which HuR normally increases. Our findings reveal that HuR may be regulating a cluster of genes involved in blood vessel formation which controls tumor angiogenesis. An approach of modulating HuR levels may overcome limitations associated with monotherapies targeting tumor vessel formation.