Abstract
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.
Highlights
The role of cancer cell FOXP3 in tumorigenesis is conflicting
The function of FOXP3 in non-small cell lung cancer (NSCLC) has not been studied and the impact of FOXP3 on the Wnt/βcatenin pathway in cancers is unknown, Here, using both in vivo, in vitro models, we have demonstrated that FOXP3 is functional as an oncogenic molecule in NSCLC and have, for the first time, demonstrated that FOXP3 can act as a co-activator to facilitate the Wntcatenin signaling pathway, inducing epithelial–mesenchymal transition (EMT) and tumor growth and metastasis in NSCLC
FOXP3 is highly expressed in NSCLC and correlated with poor prognosis To determine whether FOXP3 was expressed in NSCLC and correlated with patient prognosis, we performed immunohistochemistry on NSCLC tissues using two types of monoclonal anti-FOXP3 antibodies
Summary
The 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). In in vitro and in vivo studies, FOXP3 has been widely reported as a suppressor gene in breast cancer [7, 10,11,12] and prostate cancer [3]. Dimitrakopoulos et al found that FOXP3 expression was correlated with lymph node metastasis [13]. The function of FOXP3 in non-small cell lung cancer (NSCLC) has not been studied and the impact of FOXP3 on the Wnt/βcatenin pathway in cancers is unknown, Here, using both in vivo, in vitro models, we have demonstrated that FOXP3 is functional as an oncogenic molecule in NSCLC and have, for the first time, demonstrated that FOXP3 can act as a co-activator to facilitate the Wntcatenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC
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