FOXP3 promotes tumor growth and metastasis by activating Wnt/β-catenin signaling pathway and EMT in non-small cell lung cancer

Molecular Cancer

Research

Chang Zou¹  Shucai Yang²  Tony Mok³  Shanshan Wang⁴  Yujuan Dong⁵  Malcolm J. Underwood⁵  Innes Y. P. Wan⁵  Calvin S. H. Ng⁵  Sheng-li Yang⁶  Yi Liu⁷  George G. Chen⁸  Ming-Yue Li⁸  Li-Zhong Liu⁹  Xiang Long^1,10  Jing Du^1,10 

[1] Clinical Research Centre, Shenzhen People’s Hospital, the Second Clinical Medical College of Jinan University, Shenzhen, China;Department of Clinical Laboratory, Pingshan District People’s Hospital Of Shenzhen, Shenzhen, China;Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China;Department of Clinical Oncology, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China;Department of Otorhinolaryngology, Head and Neck Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China;Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China;Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China;Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430022, Wuhan, China;Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China;Guangdong Key Laboratory for Research and Development of Natural Drugs, Guangdong Medical University, Zhanjiang, Guangdong, China;Department of Surgery, the Chinese University of Hong Kong, Prince of Wales Hospital, Shatin, NT, Hong Kong, China;Shenzhen Research Institute, the Chinese University of Hong Kong, Shenzhen, Guangdong, China;Faculty of Medicine, Shenzhen University Health Science Center, Shenzhen University, Shenzhen, China;Peking University Shenzhen Hospital, Shenzhen, Guangdong, China;

关键词: NSCLC;    FOXP3;    EMT;    Wnt;    TCF4;   

DOI  :  10.1186/s12943-017-0700-1

 received in 2017-01-24, accepted in 2017-07-12,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundThe role of cancer cell FOXP3 in tumorigenesis is conflicting. We aimed to study FOXP3 expression and regulation, function and clinical implication in human non-small cell lung cancer (NSCLC).MethodsOne hundred and six patients with histologically-confirmed NSCLC who underwent surgery were recruited for the study. Tumor samples and NSCLC cell lines were used to examine FOXP3 and its related molecules. Various cell functions related to tumorigenesis were performed. In vivo mouse tumor xenograft was used to confirm the in vitro results.ResultsNSCLC patients with the high level of FOXP3 had a significant decrease in overall survival and recurrence-free survival. FOXP3 overexpression significantly induced cell proliferation, migration, and invasion, whereas its inhibition impaired its oncogenic function. In vivo studies confirmed that FOXP3 promoted tumor growth and metastasis. The ectopic expression of FOXP3 induced epithelial–mesenchymal transition (EMT) with downregulation of E-cadherin and upregulation of N-cadherin, vimentin, snail, slug, and MMP9. The oncogenic effects by FOXP3 could be attributed to FOX3-mediated activation of Wnt/β-catenin signaling, as FOXP3 increased luciferase activity of Topflash reporter and upregulated Wnt signaling target genes including c-Myc and Cyclin D1 in NSCLC cells. Co-immunoprecipitation results further indicated that FOXP3 could physically interacted with β-catenin and TCF4 to enhance the functions of β-catenin and TCF4, inducing transcription of Wnt target genes to promote cell proliferation, invasion and EMT induction.ConclusionsFOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.

【 授权许可】

CC BY   
© The Author(s). 2017