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Title: Mutant p53 Mediates Sensitivity to Cancer Treatment Agents in Oesophageal Adenocarcinoma Associated with MicroRNA and SLC7A11 Expression.
Austin Authors: Eichelmann, Ann-Kathrin;Mayne, George C;Chiam, Karen;Due, Steven L;Bastian, Isabell;Butz, Frederike;Wang, Tingting;Sykes, Pamela J;Clemons, Nicholas J;Liu, David Shi Hao ;Michael, Michael Z;Karapetis, Christos S;Hummel, Richard;Watson, David I;Hussey, Damian J
Affiliation: Department of General, Visceral and Transplant Surgery, University Hospital of Münster, Waldeyerstrasse 1, 48149 Münster, Germany
Peter MacCallum Cancer Centre, 305 Grattan St, Melbourne, VIC 3000, Australia
Department of Surgery, Flinders Medical Centre, Bedford Park, Adelaide, SA 5042, Australia
Flinders Health and Medical Research Institute-Cancer Program, Flinders University, Bedford Park, Adelaide, SA 5042, Australia
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC 3010, Australia
Department of Gastroenterology, Flinders Medical Centre, Bedford Park, Adelaide, SA 5042, Australia
Department of Medical Oncology, Flinders Medical Centre, Bedford Park, Adelaide, SA 5042, Australia
Department of Surgery, University Hospital of Schleswig-Holstein, Ratzeburger Allee 160, 23538 Lübeck, Germany
Issue Date: 24-May-2021 2021-05-24
Publication information: International Journal of Molecular Sciences 2021; 22(11): 5547
Abstract: 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.
DOI: 10.3390/ijms22115547
ORCID: 0000-0002-9037-7009
Journal: International Journal of Molecular Sciences
PubMed URL: 34074015
Type: Journal Article
Subjects: SLC7A11
oesophageal cancer
oestrogen receptor modulator
reactive oxidative species
Appears in Collections:Journal articles

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