The oncofetal H19 RNA connection: Hypoxia, p53 and cancer
The oncofetal H19 RNA connection: Hypoxia, p53 and cancer
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DOI：
10.1016/j.bbamcr.2010.01.010
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发表时间：
2010-04-01
影响因子：
5.1
通讯作者：
Hochberg, Abraham
中科院分区：
文献类型：
--
作者：
Matouk, Imad J.;Mezan, Shaul;Hochberg, Abraham
印迹H19基因的表达在大量人类癌症中显著升高。最近，我们报道了H19 RNA在缺氧应激中上调，并且具有致癌特性。然而，这些现象的潜在机制仍然未知。在这里，我们证明了H19 RNA升高缺氧和p53肿瘤抑制基因的状态之间的紧密相关性。野生型p53（p53（wt））防止缺氧时H19的诱导，以及防止其在p53（null）细胞中的重建。最后一种情况伴随着细胞活力的降低。p53的作用是核的，似乎独立于其四聚体。此外，使用敲低和过表达的方法，我们确定HIF 1-α作为一个关键因素，是负责H19诱导缺氧。敲低HIF 1-α消除了H19 RNA诱导，而其过表达显著增强了缺氧细胞中的H19升高。在p53（wt）缺氧细胞中，需要同时抑制p53和HIF 1-α的过表达以显著诱导H19，而每种处理单独导致轻度诱导，表明p53对H19的抑制作用的分子机制可能至少部分涉及干扰HIF 1-α活性。在体内，H19表达的显著增加发生在来源于p53（null）细胞的肿瘤中，而不是在p53（wt）细胞中。总之，我们的结果表明，p53，HIF 1-α和H19之间存在功能联系，决定了缺氧癌细胞中H19的升高。我们认为这种联系在肿瘤的发展中起着重要作用。(C)2010 Elsevier B. V.保留所有权利。
Expression of the imprinted H19 gene is remarkably elevated in a large number of human cancers. Recently, we reported that H19 RNA is up-regulated in hypoxic stress and furthermore, it possesses oncogenic properties. However, the underlying mechanism(s) of these phenomena remain(s) unknown. Here we demonstrate a tight correlation between H19 RNA elevation by hypoxia and the status of the p53 tumor suppressor. Wild type p53 (p53(wt)) prevents the induction of H19 upon hypoxia, and upon its reconstitution in p53(null) cells. The last case is accompanied by a decrease in cell viability. The p53 effect is nuclear and seems independent of its tetramerization. Furthermore, using knockdown and over-expression approaches we identified HIF1-alpha as a critical factor that is responsible for H19 induction upon hypoxia. Knocking down HIF1-alpha abolishes H19 RNA induction, while its over-expression significantly enhances the H19 elevation in hypoxic cells. In p53(wt) hypoxic cells simultaneous suppression of p53 and over-expression of HIF1-alpha are needed to induce H19 significantly, while each treatment separately resulting in a mild induction, indicating that the molecular mechanism of p53 suppression effect on H19 may at least in part involve interfering with HIF1-alpha activity. In vivo a significant increase in H19 expression occurred in tumors derived from p53(null) cells but not in p53(wt) cells. Taken together, our results indicate that a functional link exists between p53, HIF1-alpha and H19 that determines H19 elevation in hypoxic cancer cells. We suggest that this linkage plays a role in tumor development. (C) 2010 Elsevier B.V. All rights reserved.