Epigenetic silencing of AXIN2/betaTrCP and deregulation of p53-mediated control lead to wild-type β-catenin nuclear accumulation in lung tumorigenesis

R. C. Tseng, R. K. Lin, C. K. Wen, C. Tseng, H. S. Hsu, W. H. Hsu, Y. C. Wang

研究成果: 雜誌貢獻文章

32 引文 斯高帕斯(Scopus)

摘要

β-catenin accumulation is often found in lung tumors, but only a few patients have mutations in β-catenin gene. In addition, activated p53 downregulates β-catenin. Therefore, we postulated that alteration of the degradation complex AXIN2 (axis inhibition protein 2) and betaTrCP (β-transducin repeat-containing protein) and p53 regulation could result in β-catenin protein accumulation in lung cancer. Using the immunohistochemical and sequencing analyses, we found that patients with β-catenin accumulation without mutation were associated with patients with p53 overexpression and low AXIN2 expression (P=0.023∼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 (p53 wild-type) and H1299 (p53 null) lung cancer cell lines showed cooperation between p53 and AXIN2/betaTrCP in the reduction of β-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 β-catenin nuclear accumulation in non-small cell lung cancer tumorigenesis. In addition, a high level of p53 downregulates the β-catenin expression, but this effect is attenuated by non-functional AXIN2 or betaTrCP in lung cancer.

原文英語
頁(從 - 到)4488-4496
頁數9
期刊Oncogene
27
發行號32
DOIs
出版狀態已發佈 - 七月 24 2008
對外發佈Yes

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

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