Please use this identifier to cite or link to this item: https://ahro.austin.org.au/austinjspui/handle/1/26676
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
Surgery
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
Date: 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.
URI: https://ahro.austin.org.au/austinjspui/handle/1/26676
DOI: 10.3390/ijms22115547
ORCID: 0000-0002-9037-7009
0000-0001-8154-6731
0000-0002-7739-4787
0000-0001-9283-9978
0000-0002-7683-2693
0000-0002-6121-6740
Journal: International Journal of Molecular Sciences
PubMed URL: 34074015
Type: Journal Article
Subjects: SLC7A11
chemoresistance
miR-27a-3p
miRNA
oesophageal cancer
oestrogen receptor modulator
radioresistance
reactive oxidative species
ribosome
xCT
Appears in Collections:Journal articles

Show full item record

Page view(s)

30
checked on Oct 11, 2024

Google ScholarTM

Check


Items in AHRO are protected by copyright, with all rights reserved, unless otherwise indicated.