Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells
Aberrant regulation of pVHL levels by microRNA promotes the HIF/VEGF axis in CLL B cells
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DOI：
10.1182/blood-2008-10-185686
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发表时间：
2009-05-28
期刊：
影响因子：
20.3
通讯作者：
Kay, Neil E.
中科院分区：
文献类型：
--
作者：
Ghosh, Asish K.;Shanafelt, Tait D.;Kay, Neil E.
慢性淋巴细胞白血病（CLL）B细胞自分泌调节血管内皮生长因子（VEGF）的分子机制尚不清楚。在这里，我们报告说，慢性淋巴细胞白血病B细胞表达HIF-1 α的组成性水平下常氧。我们检测了负责HIF-1 α降解的von Hippel-Lindau基因产物（pVHL）的状态，发现与正常B细胞相比，CLL B细胞中pVHL的水平明显较低。我们证明了在CLL B细胞中过表达的microRNA，miR-92-1，可以靶向VHL转录物以抑制其表达。我们发现，稳定的HIF-1 α可以与转录辅激活因子p300和磷酸化的STAT 3在VEGF启动子处形成活性复合物，并募集RNA聚合酶II。这是pVHL在没有任何遗传改变的情况下可以由microRNA调节的初步证据，并解释了CLL中异常的自分泌VEGF分泌。（血。2009; 113：5568-5574）
The molecular mechanism of autocrine regulation of vascular endothelial growth factor (VEGF) in chronic lymphocytic leukemia (CLL) B cells is unknown. Here, we report that CLL B cells express constitutive levels of HIF-1 alpha under normoxia. We have examined the status of the von Hippel-Lindau gene product (pVHL) that is responsible for HIF-1 alpha degradation and found it to be at a notably low level in CLL B cells compared with normal B cells. We demonstrate that the microRNA, miR-92-1, overexpressed in CLL B cells, can target the VHL transcript to repress its expression. We found that the stabilized HIF-1 alpha can form an active complex with the transcriptional coactivator p300 and phosphorylated-STAT3 at the VEGF promoter and recruit RNA polymerase II. This is initial evidence that pVHL, without any genetic alteration, can be regulated by microRNA and explains the aberrant autocrine VEGF secretion in CLL. (Blood. 2009; 113: 5568-5574)