Autor: |
Takahiro Oike, Ken Okuda, Shunji Haruna, Akiko Shibata, Ryota Hayashi, Mayu Isono, Kohei Tateno, Nobuteru Kubo, Akihiko Uchiyama, Sei-Ichiro Motegi, Tatsuya Ohno, Yuki Uchihara, Yu Kato, Atsushi Shibata |
Jazyk: |
angličtina |
Rok vydání: |
2024 |
Předmět: |
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Zdroj: |
Advances in Radiation Oncology, Vol 9, Iss 8, Pp 101530- (2024) |
Druh dokumentu: |
article |
ISSN: |
2452-1094 |
DOI: |
10.1016/j.adro.2024.101530 |
Popis: |
Purpose: Recent radiation therapy (RT), such as intensity modulated radiation therapy and particle RT, has improved the concentration of the radiation field targeting tumors. However, severe adverse effects still occur, possibly due to genetic factors in patients. We aimed to investigate the mechanism of exacerbated inflammation during RT. Methods and Materials: Dermal fibroblasts derived from a patient with severe inflammatory adverse effects during RT were compared with 2 normal human dermal fibroblasts. Micronuclei formation, G2/M-checkpoint arrest, DNA damage signaling and repair, and inflammatory gene expression were comprehensively examined. Results: We found greater micronuclei formation in radiation-sensitive fibroblasts (RS-Fs) after ionizing radiation (IR). RS-Fs exhibited premature G2/M-checkpoint release after IR, which triggers micronuclei formation because RS-Fs undergo mitosis with unrepaired DNA double-strand breaks (DSBs). Additionally, we found that DSB end-resection and activation of the ATR-Chk1 pathway were impaired in RS-Fs after IR. Consistent with the increase in the formation of micronuclei, which can deliver cytosolic nucleic acids resulting in an innate immune response, the expression of genes associated with inflammatory responses was highly upregulated in RS-Fs after IR. Conclusions: Although this is a single case of RT-dependent adverse effect, our findings suggest that impaired G2/M-checkpoint arrest due to the lack of DSB end-resection and activation of the ATR-Chk1 pathway causes exacerbated inflammation during RT; therefore, genes involved in G2/M-checkpoint arrest may be a predictive marker for unexpected inflammatory responses in RT. |
Databáze: |
Directory of Open Access Journals |
Externí odkaz: |
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