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FOXP3 facilitates the invasion and metastasis of non-small cell lung cancer cells through regulating VEGF, EMT and the Notch1/Hes1 pathway.

ABSTRACT: Forkhead box P3 (FOXP3) is a specific marker of regulatory T cells (Tregs) that is also expressed in tumour cells. Previous studies have revealed that FOXP3 can promote metastasis in several types of cancer, including non-small cell lung cancer (NSCLC); however, the underlying mechanism of FOXP3 remains unclear. The aim of the present study was to investigate the effect of FOXP3 on vascular endothelial growth factor (VEGF), epithelial-to-mesenchymal transition (EMT) and the Notch1/Hes1 pathway in NSCLC. After FOXP3 small interfering RNA (siRNAs) were transfected into A549 cells, the expression of FOXP3 mRNA and protein was determined by reverse transcription-quantitative PCR and western blotting. Cell migration and invasion were analyzed by Transwell assays. The concentrations of matrix metalloproteinase (MMP)-2, MMP-9 and VEGF in the cell supernatant were evaluated by ELISA. The expression of relevant proteins involved in EMT and Notch1/Hes1 pathway were assessed via western blotting. Additionally, the expression of FOXP3, CD31 and E-cadherin was detected by immunohistochemical (IHC) staining of 55 human NSCLC tissue samples. The results demonstrated that FOXP3 knockdown significantly inhibited the cell migratory and invasive abilities, decreased the concentrations of MMP-2, MMP-9 and VEGF, downregulated the protein expression of vimentin, N-cadherin, Notch1 and Hes family BHLH transcription factor 1 (Hes1), and upregulated the protein expression of E-cadherin. Furthermore, FOXP3 expression was positively associated with CD31⁺ vascular endothelial cells and negatively correlated with E-cadherin in NSCLC tissues. In addition, the Notch1/Hes1 pathway inhibitor DAPT significantly downregulated the expression of FOXP3 in a dose-dependent manner. Taken together, these findings demonstrated that FOXP3 may facilitate the invasive and migratory abilities of NSCLC cells via regulating the angiogenic factor VEGF, the EMT and the Notch1/Hes1 pathway.

SUBMITTER: Li C

PROVIDER: S-EPMC8290412 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundTumour-derived exosomes have recently been shown to participate in the formation and progression of different cancer processes, including tumour microenvironment remodelling, angiogenesis, invasion, metastasis, and drug resistance. However, the function and mechanism of exosome-encapsulated nucleic acids and proteins in bladder cancer remain unclear. This study aimed to investigate the effects of tumour-derived exosomes on the tumorigenesis and development of bladder cancer.MethodsIn this study, gene expression profiles and clinical information were collected from The Cancer Genome Atlas (TCGA) database and two independent Gene Expression Omnibus (GEO) datasets. The nucleic acids and proteins encapsulated in bladder cancer-derived exosomes were obtained from the ExoCarta database. Based on these databases, the expression patterns of exosomal mRNAs and proteins and the matched clinicopathological characteristics were analysed. Furthermore, we carried out a series of experiments to verify the relevant findings.ResultsA total of 7280 differentially expressed mRNAs were found in TCGA data, of which 52 mRNAs were shown to be encapsulated in bladder cancer-derived exosomes. Survival analysis based on the UALCAN database showed that among the top 10 upregulated and the top 10 downregulated exosomal genes, only the expression of KRT6B had a statistically significant effect on the survival of bladder cancer patients. Additionally, clinical correlation analysis showed that the elevated level of KRT6B was highly associated with bladder cancer stage, grade, and metastasis status. GSEA revealed that KRT6B was involved not only in epithelial-mesenchymal transition-related pathways but also in the immune response in bladder cancer. Ultimately, our experimental results were also consistent with the bioinformatic analysis.ConclusionKRT6B, which can be detected in bladder cancer-derived exosomes, plays an important role in the epithelial-mesenchymal transition and immune responses in bladder cancer. Further research will enable its potentially prognostic marker and therapeutic target for bladder cancer.

Project description:Non-small cell lung carcinoma (NSCLC) is the most common cause of cancer‑associated mortality in the world and accounts for ~85% of human lung cancers. Metastasis‑associated protein 2 (MTA2) is a component of the histone deacetylase complex and serves a role in tumor progression; however, the mechanism through which MTA2 is involved in the progression of NSCLC remains unclear. The aim of the present study was to investigate the expression and function of MTA2 and the MTA2‑mediated signaling pathway in NSCLC cells. Expression of MTA2 and its target genes was analyzed in MTA2‑overexpressing and anti‑MTA2 antibody (AbMTA2)‑treated NSCLC cells, as well as growth, migration, invasion and apoptotic‑resistance. The inhibitory effects on tumor formation were analyzed using AbMTA2‑treated NSCLC cells and in a mouse model. Histological assessment was conducted to analyze the expressions levels of extracellular signal‑regulated kinase (ERK), RAC‑α serine/threonine protein kinase (AKT) and vascular endothelial growth factor (VEGF) in experimental tumors. Results of the present study demonstrated that MTA2 was overexpressed in NSCLC cells. The growth, migration and invasion of NSCLC cells were markedly inhibited by AbMTA2. In addition, it was observed that the ERK/AKT and VEGF signaling pathways were both upregulated in MTA2‑overexpressing NSCLC cells, and downregulated following silencing of MTA2 activation. ERK and AKT phosphorylation levels were downregulated in NSCLC cells and tumors following MTA2 silencing. The in vivo study demonstrated that tumor growth was markedly inhibited following siRNA‑MTA2 treatment. In conclusion, the results of the present study suggested that MTA2 silencing may significantly inhibit the growth and aggressiveness of NSCLC cells. Results from the present study indicated that the mechanism underlying the MTA2‑mediated invasive potential of NSCLC cells involved the ERK/AKT and VEGF signaling pathways, which may be a potential therapeutic target for the treatment of NSCLC.

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FOXP3 facilitates the invasion and metastasis of non-small cell lung cancer cells through regulating VEGF, EMT and the Notch1/Hes1 pathway.

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