Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Published: |
Nature Publishing Group
2023
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| Online Access: | http://psasir.upm.edu.my/id/eprint/106413/ |
| _version_ | 1848864760391532544 |
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| author | Ronny Sham, Nur Fatihah Abdul Hamid Hasani, Narimah Hasan, Nurhaslina Abdul Karim, Muhammad Khalis Syed Ahmad Fuad, Syed Baharom Hasbullah, Harissa Husainy Ibahim, Mohammad Johari |
| author_facet | Ronny Sham, Nur Fatihah Abdul Hamid Hasani, Narimah Hasan, Nurhaslina Abdul Karim, Muhammad Khalis Syed Ahmad Fuad, Syed Baharom Hasbullah, Harissa Husainy Ibahim, Mohammad Johari |
| author_sort | Ronny Sham, Nur Fatihah |
| building | UPM Institutional Repository |
| collection | Online Access |
| 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<jats:sup>RR_MJI</jats:sup> (acquired radioresistance) cells was developed after 8 cycles of fractionated irradiation. The development of EMT6<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> cells after exposure to 4 Gy and 8 Gy gamma-ray irradiations compared to their parental cells. Gene expression between EMT6<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> through overexpression of CTLA-4 and PD-1, and novel knowledge on therapeutic targets for recurrent radioresistant cancers. |
| first_indexed | 2025-11-15T13:53:56Z |
| format | Article |
| id | upm-106413 |
| institution | Universiti Putra Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-15T13:53:56Z |
| publishDate | 2023 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | upm-1064132024-08-08T02:49:07Z http://psasir.upm.edu.my/id/eprint/106413/ Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway Ronny Sham, Nur Fatihah Abdul Hamid Hasani, Narimah Hasan, Nurhaslina Abdul Karim, Muhammad Khalis Syed Ahmad Fuad, Syed Baharom Hasbullah, Harissa Husainy Ibahim, Mohammad Johari 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<jats:sup>RR_MJI</jats:sup> (acquired radioresistance) cells was developed after 8 cycles of fractionated irradiation. The development of EMT6<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> cells after exposure to 4 Gy and 8 Gy gamma-ray irradiations compared to their parental cells. Gene expression between EMT6<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> 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<jats:sup>RR_MJI</jats:sup> through overexpression of CTLA-4 and PD-1, and novel knowledge on therapeutic targets for recurrent radioresistant cancers. Nature Publishing Group 2023 Article PeerReviewed Ronny Sham, Nur Fatihah and Abdul Hamid Hasani, Narimah and Hasan, Nurhaslina and Abdul Karim, Muhammad Khalis and Syed Ahmad Fuad, Syed Baharom and Hasbullah, Harissa Husainy and Ibahim, Mohammad Johari (2023) Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway. Scientific Reports, 13 (1). pp. 1-12. ISSN 2045-2322 https://www.nature.com/articles/s41598-023-29925-x?error=cookies_not_supported&code=698afead-b812-4015-b8da-3e41401724f1 10.1038/s41598-023-29925-x |
| spellingShingle | Ronny Sham, Nur Fatihah Abdul Hamid Hasani, Narimah Hasan, Nurhaslina Abdul Karim, Muhammad Khalis Syed Ahmad Fuad, Syed Baharom Hasbullah, Harissa Husainy Ibahim, Mohammad Johari Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway |
| title | Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway |
| title_full | Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway |
| title_fullStr | Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway |
| title_full_unstemmed | Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway |
| title_short | Acquired radioresistance in EMT6 mouse mammary carcinoma cell line is mediated by CTLA-4 and PD-1 throughJAK/STAT/PI3K pathway |
| title_sort | acquired radioresistance in emt6 mouse mammary carcinoma cell line is mediated by ctla-4 and pd-1 throughjak/stat/pi3k pathway |
| url | http://psasir.upm.edu.my/id/eprint/106413/ http://psasir.upm.edu.my/id/eprint/106413/ http://psasir.upm.edu.my/id/eprint/106413/ |