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Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway

Cancer recurrence is often associated with the acquisition of radioresistance by cancer tissues due to failure in radiotherapy. The underlying mechanism leading to the development of acquired radioresistance in the EMT6 mouse mammary carcinoma cell line and the potential pathway involved was investi...

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Autores principales: Sham, Nur Fatihah Ronny, Hasani, Narimah Abdul Hamid, Hasan, Nurhaslina, Karim, Muhammad Khalis Abdul, Fuad, Syed Baharom Syed Ahmad, Hasbullah, Harissa Husainy, Ibahim, Mohammad Johari
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9946948/
https://www.ncbi.nlm.nih.gov/pubmed/36813833
http://dx.doi.org/10.1038/s41598-023-29925-x
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author Sham, Nur Fatihah Ronny
Hasani, Narimah Abdul Hamid
Hasan, Nurhaslina
Karim, Muhammad Khalis Abdul
Fuad, Syed Baharom Syed Ahmad
Hasbullah, Harissa Husainy
Ibahim, Mohammad Johari
author_facet Sham, Nur Fatihah Ronny
Hasani, Narimah Abdul Hamid
Hasan, Nurhaslina
Karim, Muhammad Khalis Abdul
Fuad, Syed Baharom Syed Ahmad
Hasbullah, Harissa Husainy
Ibahim, Mohammad Johari
author_sort Sham, Nur Fatihah Ronny
collection PubMed
description Cancer recurrence is often associated with the acquisition of radioresistance by cancer tissues due to failure in radiotherapy. The underlying mechanism leading to the development of acquired radioresistance in the EMT6 mouse mammary carcinoma cell line and the potential pathway involved was investigated by comparing differential gene expressions between parental and acquired radioresistance cells. EMT6 cell line was exposed to 2 Gy/per cycle of gamma-ray and the survival fraction between EMT6-treated and parental cells was compared. EMT6(RR_MJI) (acquired radioresistance) cells was developed after 8 cycles of fractionated irradiation. The development of EMT6(RR_MJI) cells was confirmed with further irradiation at different doses of gamma-ray, and both the survival fraction and migration rates were measured. Higher survival fraction and migration rates were obtained in EMT6(RR_MJI) cells after exposure to 4 Gy and 8 Gy gamma-ray irradiations compared to their parental cells. Gene expression between EMT6(RR_MJI) and parental cells was compared, and 16 genes identified to possess more than tenfold changes were selected and validated using RT-PCR. Out of these genes, 5 were significantly up-regulated i.e., IL-6, PDL-1, AXL, GAS6 and APCDD1. Based on pathway analysis software, the development of acquired radioresistance in EMT6(RR_MJI) was hypothesized through JAK/STAT/PI3K pathway. Presently, CTLA-4 and PD-1 were determined to be associated with JAK/STAT/PI3K pathway, where both their expressions were significantly increased in EMT6(RR_MJI) compared to parental cells in the 1st, 4th and 8th cycle of radiation. As a conclusion, the current findings provided a mechanistic platform for the development of acquired radioresistance in EMT6(RR_MJI) through overexpression of CTLA-4 and PD-1, and novel knowledge on therapeutic targets for recurrent radioresistant cancers.
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spelling pubmed-99469482023-02-24 Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway Sham, Nur Fatihah Ronny Hasani, Narimah Abdul Hamid Hasan, Nurhaslina Karim, Muhammad Khalis Abdul Fuad, Syed Baharom Syed Ahmad Hasbullah, Harissa Husainy Ibahim, Mohammad Johari Sci Rep Article Cancer recurrence is often associated with the acquisition of radioresistance by cancer tissues due to failure in radiotherapy. The underlying mechanism leading to the development of acquired radioresistance in the EMT6 mouse mammary carcinoma cell line and the potential pathway involved was investigated by comparing differential gene expressions between parental and acquired radioresistance cells. EMT6 cell line was exposed to 2 Gy/per cycle of gamma-ray and the survival fraction between EMT6-treated and parental cells was compared. EMT6(RR_MJI) (acquired radioresistance) cells was developed after 8 cycles of fractionated irradiation. The development of EMT6(RR_MJI) cells was confirmed with further irradiation at different doses of gamma-ray, and both the survival fraction and migration rates were measured. Higher survival fraction and migration rates were obtained in EMT6(RR_MJI) cells after exposure to 4 Gy and 8 Gy gamma-ray irradiations compared to their parental cells. Gene expression between EMT6(RR_MJI) and parental cells was compared, and 16 genes identified to possess more than tenfold changes were selected and validated using RT-PCR. Out of these genes, 5 were significantly up-regulated i.e., IL-6, PDL-1, AXL, GAS6 and APCDD1. Based on pathway analysis software, the development of acquired radioresistance in EMT6(RR_MJI) was hypothesized through JAK/STAT/PI3K pathway. Presently, CTLA-4 and PD-1 were determined to be associated with JAK/STAT/PI3K pathway, where both their expressions were significantly increased in EMT6(RR_MJI) compared to parental cells in the 1st, 4th and 8th cycle of radiation. As a conclusion, the current findings provided a mechanistic platform for the development of acquired radioresistance in EMT6(RR_MJI) through overexpression of CTLA-4 and PD-1, and novel knowledge on therapeutic targets for recurrent radioresistant cancers. Nature Publishing Group UK 2023-02-22 /pmc/articles/PMC9946948/ /pubmed/36813833 http://dx.doi.org/10.1038/s41598-023-29925-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Sham, Nur Fatihah Ronny
Hasani, Narimah Abdul Hamid
Hasan, Nurhaslina
Karim, Muhammad Khalis Abdul
Fuad, Syed Baharom Syed Ahmad
Hasbullah, Harissa Husainy
Ibahim, Mohammad Johari
Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway
title Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway
title_full Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway
title_fullStr Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway
title_full_unstemmed Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway
title_short Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 through JAK/STAT/PI3K pathway
title_sort acquired radioresistance in emt6 mouse mammary carcinoma cell line is mediated by ctla-4 and pd-1 through jak/stat/pi3k pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9946948/
https://www.ncbi.nlm.nih.gov/pubmed/36813833
http://dx.doi.org/10.1038/s41598-023-29925-x
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