p53 Inhibits Vascular Endothelial Growth Factor Expression in Solid Tumor.
p53 Inhibits Vascular Endothelial Growth Factor Expression in Solid Tumor.
复制标题
p53 抑制实体瘤中血管内皮生长因子的表达。
DOI：
10.1016/j.jss.2010.12.028
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发表时间：
2012
影响因子：
2.2
通讯作者：
Yasuhiko Yoshioka
中科院分区：
文献类型：
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作者：
Tsuchiyama A.;Ebihara M.;Kimura M.;Kitajima F.;Kotsugi M.;Itoh S.;Nagao K.;Nakamura T.;Naraoka H.;Noguchi T.;Okazaki R.;Uesugi K.;Uesugi M.;Yurimoto H.;Ireland T.R.;Sandford S.A.;Zolensky M.;Fujimura A.;Abe M.;Yada T.;Mukai T.;Okada T;Yasuhiko Yoshioka
背景p53抑癌基因是肿瘤中最常发生突变的基因之一，其突变影响肿瘤生长、细胞凋亡等多种生物学行为，在缺氧时，p53通过与缺氧诱导因子-1（hypoxia-inducible factor-1，HIF-1）相互作用而稳定。这种相互作用提高了调节HIF-1活性的p53，这仍有待阐明的可能性。METHODSFirst，我们介绍了各种类型的p53突变基因到Hep 3B和评估的作用，p53在缺氧反应，包括血管内皮生长因子（VEGF）的生产和HIF-1的激活。第二，将Hep 3B-载体细胞和Hep 3B-p53细胞皮下注射到BALB/c（nu/nu）小鼠中，并分析肿瘤进展和缺氧反应。最后，我们研究了p53突变基因在人胰腺肿瘤血管生成水平中的作用，结果显示野生型p53的表达显著抑制HIF-1活性和VEGF的产生，而p53的缺失或突变并不显著，这主要取决于HIF-1β蛋白水平。在肿瘤异种移植模型中，我们一致发现p53的缺失通过HIF-1β蛋白的积累促进VEGF的产生、新血管形成和肿瘤进展。此外，在临床胰腺肿瘤中，p53突变的肿瘤比野生型p53的肿瘤具有显著更高的血管生成水平。结论这些结果表明，p53的缺失通过调节HIF-1而有助于新生血管的形成。
BACKGROUNDThe p53 tumor-suppressor gene is one of the most frequently mutated genes in cancers, and its mutations affect various biological actions, such as tumor growth, apoptosis, and so on. During hypoxia, p53 is stabilized by interaction with hypoxia-inducible factor-1 (HIF-1). This interaction raised the possibility for regulating HIF-1 activity by p53, which is still to be elucidated.METHODSFirst, we introduced various types of the p53 mutant gene into Hep3B and evaluated the role of p53 in hypoxic responses, including vascular endothelial growth factor (VEGF) production and HIF-1 activation. Second, Hep3B-vector cells and Hep3B-p53 cells were subcutaneously injected into BALB/c (nu/nu) mice, and tumor progression and the hypoxic responses were analyzed. Finally, we investigated the role of the p53 mutant genes in the level of vascularity in human pancreatic neoplasia.RESULTSHere, we showed that expression of wild-type p53, but not null or mutated p53, significantly suppressed HIF-1 activity and production of VEGF, which mostly depends on the HIF-1β protein level. In a tumor xenograft model, we consistently found that loss of p53 promotes VEGF production, neovascularization, and tumor progression via accumulation of HIF-1β protein. Furthermore, in clinical pancreatic neoplasia, tumors with mutated p53 have significantly higher levels of vascularity than those with wild-type p53.CONCLUSIONThese results indicate that loss of p53 contributes to neovascularization through regulation of HIF-1.