Shucai Yang

BACKGROUND: 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). METHODS: One 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. RESULTS: NSCLC 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. CONCLUSIONS: FOXP3 can act as a co-activator to facilitate the Wnt-b-catenin signaling pathway, inducing EMT and tumor growth and metastasis in NSCLC.

The poor clinical outcome of hepatocellular carcinoma (HCC) patients is ascribed to the resistance of HCC cells to traditional treatments and tumor recurrence after curative therapies. Cancer stem cells (CSCs) have been identified as a small subset of cancer cells which have high capacity for self-renewal, differentiation and tumorigenesis. Recent advances in the field of liver CSCs (LCSCs) have enabled the identification of CSC surface markers and the isolation of CSC subpopulations from HCC cells. Given their central role in cancer initiation, metastasis, recurrence and therapeutic resistance, LCSCs constitute a therapeutic opportunity to achieve cure and prevent relapse of HCC. Thus, it is necessary to develop therapeutic strategies to selectively and efficiently target LCSCs. Small molecular inhibitors targeting the core stemness signaling pathways have been actively pursued and evaluated in preclinical and clinical studies. Other alternative therapeutic strategies include targeting LCSC surface markers, interrupting the CSC microenvironment, and altering the epigenetic state. In this review, we summarize the properties of CSCs in HCC and discuss novel therapeutic strategies that can be used to target LCSCs.