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Cancer Stem Cells are Regulated by STAT3 Signalling in Wilms Tumour.

ABSTRACT: The survival rates associated with Wilms tumour (WT) remain dismal despite advancements in detection and treatment strategies. Cancer stem cells (CSCs) are correlated with the initiation, recurrence and metastasis of tumours, but its impact on Wilms cancer stem cell (WCSC) maintenance remains unclear. In this study, CD133+ cells were successfully isolated from a single-cell suspension of the G401 Wilms tumour cell line using magnetic activated cell sorting (MACS). Signal transducers and activators of transcription 3 (STAT3) has been implicated in tumorigenesis, but its contribution to the metastatic progression of WCSCs has not been investigated. Here, we show that STAT3 is overexpressed in WCSCs. Activation of STAT3 in WCSCs initiated a forward feedback loop that was responsible for mediating the aggressive malignant character of Wilms tumour cells in vitro and in vivo. Treatment of CD133+ cells with stattic, a STAT3 inhibitor, also inhibited tumour formation and progression in xenograft animal models in vivo. Collectively, these studies revealed a critical role of STAT3 signalling in WCSC proliferation and motility and a role for CD133 in cancer stem-like cell function, providing evidence for CD133 as a potential therapeutic target in Wilms tumour.

SUBMITTER: Liu Y

PROVIDER: S-EPMC5929094 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo investigate the role of chemokines in Wilms tumours, especially their chemotaxis to immune cells and the role of DNA methylation in regulating the expression level of chemokines.MethodsRNAseqV2 gene expression and clinical data were downloaded from the TARGET database. DNA methylation data were downloaded from the GEO and cBioPortal database. The difference analysis and Kaplan-Meier(KM) analysis of chemokines were performed by edgeR package. Then predictive model based on chemokines was constructed by lasso regression and multivariate COX regression. ROC curve, DCA curve, Calibration curve, and Nomogram were used to evaluate the prognostic model. MCPcounter and Cibersort algorithm was used to calculate the infiltration of immune cells in Wilms tumour and para-tumour samples. Then the difference analysis of the immune cells was performed. The relationship between chemokines and immune cells were calculated by Pearson correlation. In addition, DNA methylation differences between Wilms tumour and para-tumour samples was performed. The correlation between DNA methylation and mRNA expression was calculated by Pearson correlation. Western blot(WB)and immunofluorescence were used to confirm the differential expression of CX3CL1 and T cells, and the correlation between them.ResultsA total of 16 chemokines were differentially expressed in tumour and para-tumour samples. A total of seven chemokines were associated with survival. CCL2 and CX3CL1 were positively correlated with prognosis, while high expression of CCL3, CCL8, CCL15, CCL18 and CXCL9 predicted poor prognosis. By lasso regression and multivariate COX regression, CCL3, CCL15, CXCL9 and CX3CL1 were finally included to construct a prediction model. The model shows good prediction ability. MCPcounter and Cibersort algorithm both showed that T cells were higher in para-tumour tissues than cancer tissues. Correlation analysis showed that CX3CL1 had a strong correlation with T cells. These were verified by Weston blot and immunofluorescence. DNA methylation analysis showed that various chemokines were different in para-tumours and tumours. CX3CL1 was hypermethylated in tumours, and the degree of methylation was negatively correlated with mRNA expression.Conclusion1. There is low T cell infiltration in nephroblastoma. 2. Chemokines such as CX3CL1 indicate a favourable prognosis and positively correlate with the number of T cells. 3. chemokines such as CX3CL1 are negatively regulated by DNA hypermethylation.

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Cancer Stem Cells are Regulated by STAT3 Signalling in Wilms Tumour.

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