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The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis.
Carcinogenesis. 2012 Nov; 33(11):2250-9.C

Abstract

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. However, the molecular mechanisms that regulate FoxM1 expression remain largely unknown. In the current study, we demonstrated that tumor necrosis factor (TNF)-αα 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 hypoxia-inducible factor 1 (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 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 reactive oxygen species 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 hepatocellular carcinoma tissues, and the combination of these two parameters was a powerful predictor of poor prognosis in hepatocellular carcinoma patients after curative resection. Here, we report a new molecular mechanism by which FoxM1 expression is regulated by the TNF-α/reactive oxygen species/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis.

Authors+Show Affiliations

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.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22831955

Citation

Xia, Limin, et al. "The TNF-α/ROS/HIF-1-induced Upregulation of FoxMI Expression Promotes HCC Proliferation and Resistance to Apoptosis." Carcinogenesis, vol. 33, no. 11, 2012, pp. 2250-9.
Xia L, Mo P, Huang W, et al. The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis. 2012;33(11):2250-9.
Xia, L., Mo, P., Huang, W., Zhang, L., Wang, Y., Zhu, H., Tian, D., Liu, J., Chen, Z., Zhang, Y., Chen, Z., Hu, H., Fan, D., Nie, Y., & Wu, K. (2012). The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. Carcinogenesis, 33(11), 2250-9. https://doi.org/10.1093/carcin/bgs249
Xia L, et al. The TNF-α/ROS/HIF-1-induced Upregulation of FoxMI Expression Promotes HCC Proliferation and Resistance to Apoptosis. Carcinogenesis. 2012;33(11):2250-9. PubMed PMID: 22831955.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The TNF-α/ROS/HIF-1-induced upregulation of FoxMI expression promotes HCC proliferation and resistance to apoptosis. AU - Xia,Limin, AU - Mo,Ping, AU - Huang,Wenjie, AU - Zhang,Lin, AU - Wang,Ying, AU - Zhu,Hongwu, AU - Tian,Dean, AU - Liu,Jian, AU - Chen,Zhangqian, AU - Zhang,Yongguo, AU - Chen,Zheng, AU - Hu,Hao, AU - Fan,Daiming, AU - Nie,Yongzhan, AU - Wu,Kaichun, Y1 - 2012/07/25/ PY - 2012/7/27/entrez PY - 2012/7/27/pubmed PY - 2013/1/18/medline SP - 2250 EP - 9 JF - Carcinogenesis JO - Carcinogenesis VL - 33 IS - 11 N2 - 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. However, the molecular mechanisms that regulate FoxM1 expression remain largely unknown. In the current study, we demonstrated that tumor necrosis factor (TNF)-αα 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 hypoxia-inducible factor 1 (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 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 reactive oxygen species 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 hepatocellular carcinoma tissues, and the combination of these two parameters was a powerful predictor of poor prognosis in hepatocellular carcinoma patients after curative resection. Here, we report a new molecular mechanism by which FoxM1 expression is regulated by the TNF-α/reactive oxygen species/HIF-1 pathway, and this mechanism results in the proliferation of hepatoma cells and their resistance to apoptosis. SN - 1460-2180 UR - https://www.unboundmedicine.com/medline/citation/22831955/The_TNF_α/ROS/HIF_1_induced_upregulation_of_FoxMI_expression_promotes_HCC_proliferation_and_resistance_to_apoptosis_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgs249 DB - PRIME DP - Unbound Medicine ER -