FOXP3 Is a HCC suppressor gene and Acts through regulating the TGF-β/Smad2/3 signaling pathway

BMC Cancer

Research Article

Ji-Wei Zhang¹  Ying-Jun Zhao¹  Ya Cao²  Xiaoming Zhang³  Xiao-Ying Wang⁴  Meng Duan⁴  Zhen-Bin Ding⁴  Jie-Yi Shi⁴  Li-Jie Ma⁴  Qiang Gao⁴  Liu-Xiao Yang⁴  Jian Zhou⁵  Jia Fan⁵ 

[1]Cancer Research Institute, Fudan University Shanghai Cancer Center, Shanghai, People’s Republic of China

[2]Cancer Research Institute, Xiangya School of Medicine, Central South University, Changsha, Hunan, People’s Republic of China

[3]Key Laboratory of Molecular Virology & Immunology, Institut Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai, People’s Republic of China

[4]Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, 200032, Shanghai, People’s Republic of China

[5]Liver Cancer Institute, Zhongshan Hospital, and Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), Fudan University, 180 Fenglin Road, 200032, Shanghai, People’s Republic of China

[6]Institute of Biomedical Sciences, Fudan University, Shanghai, People’s Republic of China

关键词: FOXP3;    Hepatocellular carcinoma;    TGF-β;    Prognosis;    ChIP;   

DOI  :  10.1186/s12885-017-3633-6

 received in 2017-03-19, accepted in 2017-08-28,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundFOXP3 has been discovered to be expressed in tumor cells and participate in the regulation of tumor behavior. Herein, we investigated the clinical relevance and biological significance of FOXP3 expression in human hepatocellular carcinoma (HCC).MethodsExpression profile of FOXP3 was analyzed using real-time RT-PCR, western blotting and immunofluorescence on HCC cell lines, and immunostaing of a tissue microarray containing of 240 primary HCC samples. The potential regulatory roles of FOXP3 were dissected by an integrated approach, combining biochemical assays, analysis of patient survival, genetic manipulation of HCC cell lines, mouse xenograft tumor models and chromatin immunoprecipitation (ChIP) sequencing.ResultsFOXP3 was constitutively expressed in HCC cells with the existence of splice variants (especially exon 3 and 4 deleted, Δ3,4-FOXP3). High expression of FOXP3 significantly correlated with low serum α-fetoprotein (AFP) level, absence of vascular invasion and early TNM stage. Survival analyses revealed that increased FOXP3 expression was significantly associated with better survival and reduced recurrence, and served as an independent prognosticator for HCC patients. Furthermore, FOXP3 could potently suppress the proliferation and invasion of HCC cells in vitro and reduce tumor growth in vivo. However, Δ3,4-FOXP3 showed a significant reduction in the tumor-inhibiting effect. The inhibition of FOXP3 on HCC aggressiveness was acted probably by enhancing the TGF-β/Smad2/3 signaling pathway.ConclusionOur findings suggest that FOXP3 suppresses tumor progression in HCC via TGF-β/Smad2/3 signaling pathway, highlighting the role of FOXP3 as a prognostic factor and novel target for an optimal therapy against this fatal malignancy.

【 授权许可】

CC BY   
© The Author(s). 2017