Ribonucleotide reductase small subunit p53R2 promotes oral cancer invasion via the E-cadherin/β-catenin pathway
Ribonucleotide reductase small subunit p53R2 promotes oral cancer invasion via the E-cadherin/β-catenin pathway
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DOI：
10.1016/j.oraloncology.2008.07.005
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发表时间：
2009-06-01
期刊：
影响因子：
4.8
通讯作者：
Mizuno, Akio
中科院分区：
文献类型：
--
作者：
Yanamoto, Souichi;Kawasaki, Goro;Mizuno, Akio
p53诱导型p53 R2基因已被分离出来，并显示在DNA损伤后的DNA修复和合成中起关键作用。此外，据报道，p53 R2的表达和活性与人癌细胞的抗癌剂抗性相关。以前，我们报道p53 R2表达的存在是区域淋巴结转移的预测因子在口腔鳞状细胞癌，然而，p53 R2表达的癌症转移的机制仍然不清楚。在本研究中，我们分析了p53 R2表达与肿瘤体外侵袭的相关性。培养人口腔癌细胞系SAS、HSC-3和Ca 9 -22，并使用Matrigel侵袭试验评估这些癌细胞的侵袭潜力。为了研究p53 R2在肿瘤侵袭中的作用，通过小干扰RNA（siRNA）检测p53 R2的下调。此外，我们研究了细胞粘附分子（E-钙粘蛋白和β-连环蛋白）在癌细胞的亚细胞提取物的免疫印迹细胞内定位。明胶酶谱法测定基质金属蛋白酶（MMPs）的蛋白水解活性。p53 R2的下调显著增强了p53突变型癌细胞的侵袭能力（p < 0.01），并增强了B-连环蛋白的核转位，而p53野生型癌细胞中的总细胞E-钙粘蛋白表达丧失。p53 R2 siRNA转染的侵袭指数的这些变化并不伴随MMP活性和表达的改变。提示p53 R2的表达可能与癌细胞的侵袭有关，p53 R2可能通过E-cadherin/beta-catenin途径促进癌细胞的侵袭，而不影响MMP的活性。(C)2008爱思唯尔有限公司保留所有权利。
The p53-inducible p53R2 gene has been isolated and shown to play a crucial role in DNA repair and synthesis after DNA damage. Moreover, the expression and activity of p53R2 has been reported to be associated with the anticancer agent resistance of human cancer cells. Previously, we reported that the presence of p53R2 expression was a predictive factor for regional lymph node metastasis in oral squamous cell carcinoma; however, the mechanism of cancer metastasis by p53R2 expression is still unclear. In the present study, we analyzed the correlation of p53R2 expression with cancer invasion in vitro. Three human oral cancer cell lines (SAS, HSC-3 and Ca9-22) were cultured, and the invasive potential of these cancer cells was evaluated using Matrigel invasion assay. To investigate the effect of p53R2 on cancer invasion, the down-regulation of p53R2 was examined by small interfering RNA ( siRNA). Moreover, we examined the intracellular localization of cell adhesion molecules (E-cadherin and beta-catenin) in subcellular extractions of cancer cells by immunoblotting. The proteolytic activity of matrix metalloproteinases (MMPs) was assessed by gelatin zymography. Down-regulation of p53R2 significantly enhanced the invasion potential ( p < 0.01), and enhanced nuclear translocation of b- catenin with loss of total cellular E-cadherin expression in p53 mutant cancer cells, but not in p53 wild-type cancer cells. These changes in the invasion index by p53R2 siRNA transfection were not accompanied by alterations in MMP activity and expression. These results suggested that the expression of p53R2 could be associated with the invasion of cancer cells, and indicated that p53R2 might promote cancer invasion via the E-cadherin/beta-catenin pathway without the alteration of MMP activity. (C) 2008 Elsevier Ltd. All rights reserved.