ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis.
ΔNp63 promotes pediatric neuroblastoma and osteosarcoma by regulating tumor angiogenesis.
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DOI：
10.1158/0008-5472.can-13-0894
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发表时间：
2014-01-01
期刊：
影响因子：
11.2
通讯作者：
Cam H
中科院分区：
文献类型：
--
作者：
Bid HK;Roberts RD;Cam M;Audino A;Kurmasheva RT;Lin J;Houghton PJ;Cam H
抑癌基因P53及其家族成员p63/p73是肿瘤发生的关键决定因素。Δnp63是p63的一个剪接变异体，它缺少N端的反式激活结构域。它被认为可以拮抗P53、P63和P73依赖的翻译，从而阻断它们的肿瘤抑制活性。在我们对儿童实体瘤、神经母细胞瘤和骨肉瘤的研究中，我们发现了ΔNp63的过度表达，但ΔNp63的表达与P53的突变状态无关。我们的数据表明，ΔNp63本身赋予细胞一种导致恶性转化的功能，这一功能独立于任何P53拮抗剂。在这里，我们证明了ΔNp63的过度表达，不依赖于P53，增加了IL-6和IL-8的分泌，导致STAT-3(Tyr705)的磷酸化增加。我们发现STAT-3的磷酸化水平升高导致HIF-1α蛋白的稳定，从而导致血管内皮生长因子的分泌。我们还展示了人类的临床数据，这表明了ΔNp63在骨肉瘤转移中的机制作用。综上所述，我们的研究揭示了ΔNp63作为主要转录因子调控肿瘤血管生成的机制。
The tumor suppressor gene p53 and its family members p63/p73 are critical determinants of tumorigenesis. ΔNp63 is a splice variant of p63, which lacks the N-terminal transactivation domain. It is thought to antagonize p53-, p63- and p73- dependent translation, thus blocking their tumor suppressor activity. In our studies of the pediatric solid tumors neuroblastoma and osteosarcoma, we find overexpression of ΔNp63; however, there is no correlation of ΔNp63 expression with p53 mutation status. Our data suggest that ΔNp63 itself endows cells with a gain of function that leads to malignant transformation, a function independent of any p53 antagonism. Here, we demonstrate that ΔNp63 overexpression, independent of p53, increases secretion of interleukin-6 (IL-6) and interleukin-8 (IL-8), leading to elevated phosphorylation of STAT-3 (Tyr-705). We show that elevated phosphorylation of STAT-3 leads to stabilization of HIF-1α protein, resulting in VEGF secretion. We also show human clinical data, which suggests a mechanistic role for ΔNp63 in osteosarcoma metastasis. In summary, our studies reveal the mechanism by which ΔNp63, as a master transcription factor, modulates tumor angiogenesis.