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Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microRNA and SLC7A11 expression

ABSTRACT: Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microRNA and SLC7A11 expression

PROVIDER: PRJNA721462 | ENA |

REPOSITORIES: ENA

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Mutant p53 mediates sensitivity to cancer treatment agents in oesophageal adenocarcinoma associated with microRNA and SLC7A11 expression

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

Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression.

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.

| S-EPMC8197322 | biostudies-literature

Super-enhancer-driven MLX mediates redox balance maintanance via SLC7A11 in osteosarcoma

Project description:A systematic analysis of super-enhancers identified MLX as a potential oncogene in osteosarcoma. Knockdown of MLX impaired tumor aggressiveness in vitro and in vivo, suggesting oncogenic properties of MLX. Mechanistically, silencing of MLX downregulates SLC7A11, a key gene encoding glutamate/cystine antiporter, to attenuate the uptake of cystine and interrupt the redox balance, leading to ferroptotic cell death. Pharmacological inhibition of SLC7A11 triggered massive ferroptosis and caused impaired tumor growth, providing a promising approach for osteosarcoma treatment.

2023-08-08 | GSE220173 | GEO

Organismal sensitivity to environmental agents induced toxicity: A comparative ecotoxicogenomics approach

Project description:Organismal sensitivity to environmental agents induced toxicity: A comparative ecotoxicogenomics approach

| PRJNA384181 | ENA

LncRNA SLC7A11-AS1 suppresses ferroptosis in hepatocellular carcinoma to promote tumorigenesis

Project description:LncRNAs are playing essential roles in epigenetic regulation, mRNA translation, and protein modification. However, the function of SLC7A11-AS1, an antisense lncRNA derived from the solute carrier family 7 member 11 (SLC7A11) gene, remains incompletely known. In this study, we utilized shRNA technology to knock down SLC7A11-AS1 in HepG2 cells, aiming to investigate the role of SLC7A11-AS1 in hepatocellular carcinoma. RNA-seq results revealed that there were 2536 differentially expressed genes upon SLC7A11-AS1 knockdown.

2024-07-17 | GSE244762 | GEO

Gene induction by low pH in oesophageal cells

Project description:Differential gene expression analysis of oesophageal cells stimulated with a low pH environment. Study designed to identify pathways involved in progression of gastro-oesophageal reflux disease through Barrett's oesophagus to adenocarcinoma. Identified many subsets of genes with involvement in pathogenesis. Keywords = GORD Keywords = Barrett's Oesophagus Keywords = Oesopageal Adenocarcinoma. Keywords: time-course

2005-10-04 | GSE2144 | GEO

Genome-Wide DNA Methylation Profiling of Oesophageal Cancer-Associated Myofibroblasts

Project description:The Illumina Infinium HumanMethylation450 BeadChip arrays were performed on a collection of primary oesophageal cancer-associated myofibroblasts (CAM) and their patient-matched adjacent tissue myofibroblasts (ATM). CAM and ATM samples were obtained from patients with oesophageal adenocarcinomas undergoing cancer surgery.

2019-01-10 | GSE97687 | GEO

RNAseq of Oesophageal Adenocarcinoma Cell Lines

Project description:rna sequencing of Oesophageal Adenocarcinoma Cell lines: OACP4, OE19, FLO-1, SK-GT-4, ESO26, OE33, ESO51, OACM5.1 C, JH-EsoAd1

2022-06-01 | GSE153096 | GEO

Oesophageal adenocarcinoma global proteomes

Project description:We present data of global proteomes for oesophageal adenocarcinoma and for normal adjacent tissue from seven donors.

2024-12-17 | PXD054428 | Pride

EZH2 protects mucosal melanoma from ferroptosis via the KLF14-SLC7A11 signaling pathway (RNA-Seq)

Project description:Background: Mucosal melanoma (MM) is epidemiologically, biologically, and molecularly distinct from cutaneous melanoma. Current treatment strategies have failed to significantly improve the prognosis for MM patients. This study aims to identify therapeutic targets and develop combination strategies by investigating the mechanisms underlying the tumorigenesis and progression of MM. Methods: We analyzed the copy number amplification of EZH2 in 547 melanoma patients and investigated its correlation with clinical prognosis. Utilizing cell lines, organoids, and patient-derived xenograft models, we assessed the impact of EZH2 on cell proliferation and sensitivity to ferroptosis. Further, we explored the mechanisms of ferroptosis resistance associated with EZH2 by conducting RNA sequencing and chromatin immunoprecipitation sequencing. Results: EZH2 copy number amplification was closely associated with malignant phenotype and poor prognosis in MM patients. EZH2 was essential for MM cell proliferation in vitro and in vivo. Moreover, genetic perturbation of EZH2 rendered MM cells sensitized to ferroptosis. Combination treatment of EZH2 inhibitor with ferroptosis inducer significantly inhibited the growth of MM. Mechanistically, EZH2 inhibited the expression of KLF14, which binds to the promoter of SLC7A11 to repress its transcription. Loss of EZH2 therefore reduced the expression of SLC7A11, leading to reduced intracellular SLC7A11-dependent glutathione synthesis to promote ferroptosis. Conclusion: Our findings not only establish EZH2 as a biomarker for MM prognosis, but also highlight the EZH2-KLF14-SLC7A11 axis as a potential target for MM treatment.

2024-06-20 | GSE269789 | GEO

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