Reduced p21WAF1/CIP1 via alteration of p53-DDX3 pathway is associated with poor relapse-free survival in early-stage human papillomavirus-associated lung cancer

De Wei Wu, Wen Shan Liu, John Wang, Chih Yi Chen, Ya Wen Cheng, Huei Lee

研究成果: 雜誌貢獻文章同行評審

69 引文 斯高帕斯(Scopus)

摘要

Purpose: DDX3 alteration has been shown to participate in hepatocellular tumorigenesis via p21WAF1/CIP1 (p21) deregulation. We observed that DDX3 and p21 expression in lung tumors was negatively associated with E6 expression. Therefore, the aim of this study was to clarify whether deregulation of p21 by DDX3 via an E6-inactivated p53 pathway would enhance tumor progression in HPV-associated lung cancers. Experimental Design: Real-time PCR, luciferase assays, immunoprecipitation, and chromatin immunoprecipitation (ChIP) were performed to determine whether DDX3 was regulated by p53 to synergistically enhance p21 transcriptional activity. Cell proliferation was examined by cell counting and colony formation assays. DDX3 and p21 expression were evaluated in 138 lung tumors by real-time PCR and immunohistochemistry. The prognostic value of p21 expression on relapse-free survival (RFS) was analyzed by Kaplan-Meier analysis. Results: Real-time PCR, luciferase assays, and ChIP assays indicated that three putative p53 binding sites, located at -1,080/-1,070, -695/-685, and -283/-273 on the DDX3 promoter, were required for DDX3 transcription. DDX3 deregulation by the E6-inactivated p53 pathway could promote cell proliferation and the ability to form colonies via reduced Sp1 binding activity on the p21 promoter. Among tumors, p21 expression was positively associated with DDX3 expression and negatively related with E6 expression, particularly in early-stage (I + II) tumors. Interestingly, low p21 expression was associated with a poor RFS in early-stage lung cancer. Conclusion: The reduction of p21 by the alteration of the p53-DDX3 pathway plays an essential role in early-stage HPV-associated lung tumorigenesis and is correlated with poor RFS of lung cancer patients.
原文英語
頁(從 - 到)1895-1905
頁數11
期刊Clinical Cancer Research
17
發行號7
DOIs
出版狀態已發佈 - 四月 1 2011
對外發佈

ASJC Scopus subject areas

  • 癌症研究
  • 腫瘤科

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