Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors.
Characterization of ΔNp73 expression and regulation in gastric and esophageal tumors.
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DOI：
10.1038/onc.2010.319
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发表时间：
2010-10-28
期刊：
影响因子：
8
通讯作者：
Zaika, A.
中科院分区：
文献类型：
--
作者：
Vilgelm, A. E.;Hong, S-M;Washington, M. K.;Wei, J.;Chen, H.;El-Rifai, W.;Zaika, A.
p73 是 p53 蛋白家族的成员。尽管p53的肿瘤抑制功能已被明确定义，但p73在肿瘤发生中的作用仍然存在争议。 p73 亚型的复杂表达模式使得难以明确解释实验结果。此前，我们和其他人发现 p73 的 N 端截短亚型 ΔNp73 在体外和体内具有有效的抗凋亡和致癌特性。在本研究中，我们首次分析了ΔNp73在大量胃、胃食管交界处和食管肿瘤中的调节作用。我们发现这些肿瘤中 ΔNp73 mRNA 和蛋白的表达增加。此外，ΔNp73蛋白的上调与患者生存率低显着相关。通过发现 ΔNp73 促进软琼脂中胃上皮细胞的贴壁独立生长，进一步证实了 ΔNp73 的致癌特性。由于目前对 ΔNp73 转录的调控知之甚少，我们研究了介导 ΔNp73 表达的替代 p73 基因启动子。通过计算机分析 ΔNp73 启动子以及使用染色质免疫沉淀、定点突变和缺失分析，我们确定了 ΔNp73 启动子内包含 HIC1 蛋白结合位点的进化保守区域。我们发现 HIC1 负向调节粘膜上皮细胞中 ΔNp73 的转录。这导致 ΔNp73 蛋白水平降低，通常可以控制 ΔNp73 亚型的致癌潜力。
p73 is a member of the p53 protein family. Although the tumor suppressor function of p53 is clearly defined, the role of p73 in tumorigenesis is still a matter of debate. A complex pattern of expression of p73 isoforms makes it difficult to unambiguously interpret the experimental results. Previously, we and others have found that the N-terminally truncated isoform of p73, ΔNp73, has potent anti-apoptotic and oncogenic properties in vitro and in vivo. In the present study, we analyzed, for the first time, the regulation of ΔNp73 in a large number of gastric, gastroesophageal junction and esophageal tumors. We found that expression of ΔNp73 mRNA and protein is increased in these neoplasms. Furthermore, the up-regulation of the ΔNp73 protein is significantly associated with poor patient survival. Oncogenic properties of ΔNp73 were further confirmed by finding that ΔNp73 facilitates anchorage-independent growth of gastric epithelial cells in soft agar. As little is currently known about the regulation of ΔNp73 transcription, we investigated the alternative p73 gene promoter that mediates the ΔNp73 expression. Analyzing the ΔNp73 promoter in silico as well as by using chromatin immunoprecipitation, site-directed mutagenesis and deletion analyses we identified the evolutionary conserved region within the ΔNp73 promoter that contains binding sites for HIC1 protein. We found that HIC1 negatively regulates ΔNp73 transcription in mucosal epithelial cells. This leads to a decrease in ΔNp73 protein levels and may normally control the oncogenic potential of the ΔNp73 isoform.
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