Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis
Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis
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DOI：
10.1038/onc.2008.83
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发表时间：
2008-07-24
期刊：
影响因子：
8
通讯作者：
Wang, Y-C
中科院分区：
文献类型：
--
作者：
Tseng, R-C;Lin, R-K;Wang, Y-C
β -连环蛋白积聚常见于肺肿瘤，但只有少数患者β -连环蛋白基因发生突变。此外，活化的p53下调β -连环蛋白。因此，我们假设降解复合体AXIN2（轴抑制蛋白2）和betaTrCP （β -转导重复序列包含蛋白）以及p53调控的改变可能导致肺癌中β -连环蛋白的积累。通过免疫组织化学和测序分析，我们发现β -catenin积累无突变的患者与p53过表达和AXIN2低表达的患者相关（P=0.023相似于0.041）。AXIN2的改变与早期患者的生存差相关（P=0.016）。AXIN2和betaTrCP的低表达与启动子超甲基化和组蛋白去乙酰化显著相关。p53、AXIN2和betaTrCP基因在A549 （p53野生型）和H1299 （p53无型）肺癌细胞系中的异位表达和敲低表明p53与AXIN2/betaTrCP协同降低β -连环蛋白的表达。我们的临床和细胞模型研究结果提供了新的证据，证明降解复合体中AXIN2/betaTrCP的表观遗传沉默和p53介导控制的解除导致非小细胞肺癌肿瘤发生中野生型β -连环蛋白核积累。此外，高水平的p53下调了β -连环蛋白的表达，但这种作用在肺癌中被无功能的AXIN2或betaTrCP减弱。
beta-catenin accumulation is often found in lung tumors, but only a few patients have mutations in beta-catenin gene. In addition, activated p53 downregulates beta-catenin. Therefore, we postulated that alteration of the degradation complex AXIN2 ( axis inhibition protein 2) and betaTrCP (beta-transducin repeat-containing protein) and p53 regulation could result in beta-catenin protein accumulation in lung cancer. Using the immunohistochemical and sequencing analyses, we found that patients with beta-catenin accumulation without mutation were associated with patients with p53 overexpression and low AXIN2 expression (P=0.023 similar to 0.041). Alteration of AXIN2 was associated with poor survival in early stage patients (P=0.016). Low expression of AXIN2 and betaTrCP was significantly associated with promoter hypermethylation and histone deacetylation. Ectopic expression and knockdown of p53, AXIN2 and betaTrCP genes in A549 (p53wild-type) and H1299 (p53 null) lung cancer cell lines showed cooperation between p53 and AXIN2/betaTrCP in the reduction of beta-catenin expression. Our clinical and cell model findings provide new evidence that epigenetic silencing of AXIN2/betaTrCP in the degradation complex and deregulation of p53-mediated control lead to wild-type beta-catenin nuclear accumulation in non-small cell lung cancer tumorigenesis. In addition, a high level of p53 downregulates the beta-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer.