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The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis.
MedLine Citation:
PMID:  22831955     Owner:  NLM     Status:  Publisher    
The proliferation-specific transcription factor Forkhead box M1 (FoxM1) acts as a master regulator of cancer cell growth and survival and plays an important role in the development of hepatocellular carcinoma (HCC). However, the molecular mechanisms that regulate FoxM1 expression remain largely unknown. In the current study, we demonstrated that TNF-α induced FoxM1 expression and transactivated its promoter activity in hepatoma cells. Serial 5' deletion and site-directed mutagenesis revealed that the induction of FoxM1 expression by TNF-α was dependent upon the HIF1-1 and HIF1-3/4 binding sites within the FoxM1 promoter. Furthermore, at the transcriptional level, the stabilization of HIF-1α via reactive oxygen species (ROS) generation led to the binding of HIF-1α to the FoxM1 promoter and resulted in increased FoxM1 expression. The inhibition of both HIF-1α expression and ROS generation significantly decreased TNF-α-induced FoxM1 overexpression. Consequently, the upregulation of FoxM1 promoted the proliferation of hepatoma cells and enhanced their resistance to TNF-α-induced apoptosis. Consistently, there was a positive correlation between HIF-1α and FoxM1 expression in 406 human HCC tissues, and the combination of these two parameters was a powerful predictor of poor prognosis in HCC patients after curative resection. Here, we report a new molecular mechanism by which FoxM1 expression is regulated by the TNF-α/ROS/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis.
Limin Xia; Ping Mo; Wenjie Huang; Lin Zhang; Ying Wang; Hongwu Zhu; Dean Tian; Jian Liu; Zhangqian Chen; Yongguo Zhang; Zheng Chen; Hao Hu; Daiming Fan; Yongzhan Nie; Kaichun Wu
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-7-25
Journal Detail:
Title:  Carcinogenesis     Volume:  -     ISSN:  1460-2180     ISO Abbreviation:  -     Publication Date:  2012 Jul 
Date Detail:
Created Date:  2012-7-26     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  8008055     Medline TA:  Carcinogenesis     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Fourth Military Medical University, Xi'an 710032, Shaanxi Province, People's Republic of China.
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