Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microRNA and SLC7A11 expression
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ABSTRACT:
PROVIDER: PRJNA721462 | ENA |
REPOSITORIES: ENA
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Project description:1) Background: TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. (2) Methods: Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. (3) Results: Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p<0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p=0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the predicted mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes as well as in p53 signalling pathways. (4) Discussion: These results provide a better understanding of the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-gluthatione axis may represent a promising approach to overcome resistance associated with mut-p53.
2021-05-31 | GSE171965 | GEO
Project description:TP53 gene mutations occur in 70% of oesophageal adenocarcinomas (OACs). Given the central role of p53 in controlling cellular response to therapy we investigated the role of mutant (mut-) p53 and SLC7A11 in a CRISPR-mediated JH-EsoAd1 TP53 knockout model. Response to 2 Gy irradiation, cisplatin, 5-FU, 4-hydroxytamoxifen, and endoxifen was assessed, followed by a TaqMan OpenArray qPCR screening for differences in miRNA expression. Knockout of mut-p53 resulted in increased chemo- and radioresistance (2 Gy survival fraction: 38% vs. 56%, p < 0.0001) and in altered miRNA expression levels. Target mRNA pathways analyses indicated several potential mechanisms of treatment resistance. SLC7A11 knockdown restored radiosensitivity (2 Gy SF: 46% vs. 73%; p = 0.0239), possibly via enhanced sensitivity to oxidative stress. Pathway analysis of the mRNA targets of differentially expressed miRNAs indicated potential involvement in several pathways associated with apoptosis, ribosomes, and p53 signaling pathways. The data suggest that mut-p53 in JH-EsoAd1, despite being classified as non-functional, has some function related to radio- and chemoresistance. The results also highlight the important role of SLC7A11 in cancer metabolism and redox balance and the influence of p53 on these processes. Inhibition of the SLC7A11-glutathione axis may represent a promising approach to overcome resistance associated with mut-p53.
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Project description:rna sequencing of Oesophageal Adenocarcinoma Cell lines: OACP4, OE19, FLO-1, SK-GT-4, ESO26, OE33, ESO51, OACM5.1 C, JH-EsoAd1
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Project description:Open chromatin profiling (ATAC-seq) of human oesophageal adenocarcinoma patient samples.
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Project description:Exosomes were purified from 250 ul serum using ExoQuickTm. The presence of particles consistent in size with exosomes (60-150nm) was confirmed using a Nanosight LM10. miRNA was extracted from exosomes using an miRNeasy Serum/Plasma kit (Qiagen, #217184). miRNA was reversed transcribed using a TaqMan® microRNA Reverse Transcription Kit (Life technologies, #4366596). miRNA profiling was performed with a high throughput TaqMan® OpenArray® Human microRNA panel (Life technologies, #4461104). The panel consisted of probes for 754 human miRNAs that are based on miRNA sequences derived from Sanger miRBase v14. MegaplexTM Primer Human Pool A v2.1 and Human Pool B v2.0 or v3.0 The poor prognosis and rising incidence of oesophageal adenocarcinoma highlight the need for improved methods for detection of this cancer. Molecular biomarkers offer potential for this. The potential for circulating miRNAs as biomarkers in some other cancers has been shown, but circulating miRNAs have not been well characterized in oesophageal adenocarcinoma. This study investigated whether circulating miRNAs could be used to detect oesophageal adenocarcinoma.
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Project description:We present data from tissues of seven oesophageal adenocarcinomas of CD4 and CD8 T cell epitopes eluted from the cell surface using mass spectrometry (immunopeptidomics) of presented HLA bound peptides.This dataset forms part of the publication:Nicholas, B., Bailey, A., McCann, K.J., Wood, O., Walker, R.C., Parker, R., Ternette, N., Elliott, T., Underwood, T.J., Johnson, P. and Skipp, P. (2022), Identification of neoantigens in esophageal adenocarcinoma. Immunology. Accepted Author Manuscript. https://doi.org/10.1111/imm.13578
2022-09-27 | PXD031108 | Pride
Project description:Oesophageal cancer is the ninth most common cancer in the UK and accounts for 5% of all cancer deaths. The incidence of the disease in men has risen 50% in the last 25 years with the commonest pathological subtype in the West being adenocarcinoma, while in East Asia oesophageal squamous cell carcinoma predominates. Despite efforts to screen for Barrett’s oesophagus, and pre-operatively select OAC patients who are likely to benefit from potentially curative surgery, survival remains poor. The five year survival rate is less than 17% and even in early stage locoregional confined disease this figure lies between 25-35%. A significant improvement in overall survival has been demonstrated with neo-adjuvant or peri-operative chemotherapy but the optimal approach for individual patients remains unclear. A consistent finding has been that complete histopathological response to neo-adjuvant chemotherapy is a prognostic biomarker for increased survival benefit. Therefore, there is a pressing need to identify biomarkers capable of predicting response, enabling clinicians to select patients for whom neo-adjuvant therapies would be beneficial. This experiment represents gene expression profiling of 60 pre-treatment formalin-fixed paraffin embedded (FFPE) oesophageal adenocarcinoma biopsies. All patients were treated with neo-adjuvant cisplatin-based chemotherapy prior to surgical resection at the Northern Ireland Cancer Centre from 2004-2012. The aim of the experiment was to carry out functional enrichment of pathological responders and non-responders to neo-adjuvant chemotherapy in order to identify novel mechanism of drug resistance or chemo-sensitivity.
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Project description:Selective markers are needed for earlier diagnosis, optimal staging and treatment of oesophageal adenocarcinoma. This quantitative shotgun proteomic study used patient-matched fresh frozen tissue samples of OAC, normal oesophagus and normal stomach.
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