IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma
Predicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for ra...
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| Format: | Article |
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Frontiers Media S.A.
2021-06-01
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| Series: | Frontiers in Oncology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fonc.2021.647175/full |
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| author | Chih-Chia Yu Chih-Chia Yu Michael W.Y. Chan Michael W.Y. Chan Michael W.Y. Chan Michael W.Y. Chan Hon-Yi Lin Hon-Yi Lin Wen-Yen Chiou Wen-Yen Chiou Ru-Inn Lin Chien-An Chen Moon-Sing Lee Moon-Sing Lee Chen-Lin Chi Chen-Lin Chi Liang-Cheng Chen Liang-Cheng Chen Li-Wen Huang Li-Wen Huang Chia-Hui Chew Chia-Hui Chew Feng-Chun Hsu Hsuan-Ju Yang Shih-Kai Hung Shih-Kai Hung |
| author_facet | Chih-Chia Yu Chih-Chia Yu Michael W.Y. Chan Michael W.Y. Chan Michael W.Y. Chan Michael W.Y. Chan Hon-Yi Lin Hon-Yi Lin Wen-Yen Chiou Wen-Yen Chiou Ru-Inn Lin Chien-An Chen Moon-Sing Lee Moon-Sing Lee Chen-Lin Chi Chen-Lin Chi Liang-Cheng Chen Liang-Cheng Chen Li-Wen Huang Li-Wen Huang Chia-Hui Chew Chia-Hui Chew Feng-Chun Hsu Hsuan-Ju Yang Shih-Kai Hung Shih-Kai Hung |
| author_sort | Chih-Chia Yu |
| collection | DOAJ |
| description | Predicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for radiation sensitivity. We identified IRAK2, a key immune mediator of the IL-1R/TLR signaling, as a potential target in investigating radiosensitivity. In four OSCC cell lines, we observed that intrinsically low IRAK2 expression demonstrated a radioresistant phenotype (i.e., OML1-R and SCC4), and vice versa (i.e., OML1 and SCC25). Next, we overexpressed IRAK2 in low IRAK2-expression OSCC cells and knocked it down in high IRAK2-expression cells to examine changes of irradiation response. After ionizing radiation (IR) exposure, IRAK2 overexpression enhanced the radiosensitivity of radioresistant cells and synergistically suppressed OSCC cell growth both in vitro and in vivo, and vice versa. We found that IRAK2 overexpression restored and enhanced radiosensitivity by enhancing IR-induced cell killing via caspase-8/3-dependent apoptosis. OSCC patients with high IRAK2 expression had better post-irradiation local control than those with low expression (i.e., 87.4% vs. 60.0% at five years, P = 0.055), showing that IRAK2 expression was associated with post-radiation recurrence. Multivariate analysis confirmed high IRAK2 expression as an independent predictor for local control (HR, 0.11; 95% CI, 0.016 – 0.760; P = 0.025). In conclusion, IRAK2 enhances radiosensitivity, via modulating caspase 8/3-medicated apoptosis, potentially playing double roles as a predictive biomarker and a novel therapeutic target in OSCC. |
| first_indexed | 2024-12-19T03:10:41Z |
| format | Article |
| id | doaj.art-3464f35b21564d81bfbb76d1b37356bc |
| institution | Directory Open Access Journal |
| issn | 2234-943X |
| language | English |
| last_indexed | 2024-12-19T03:10:41Z |
| publishDate | 2021-06-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Oncology |
| spelling | doaj.art-3464f35b21564d81bfbb76d1b37356bc2022-12-21T20:38:00ZengFrontiers Media S.A.Frontiers in Oncology2234-943X2021-06-011110.3389/fonc.2021.647175647175IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell CarcinomaChih-Chia Yu0Chih-Chia Yu1Michael W.Y. Chan2Michael W.Y. Chan3Michael W.Y. Chan4Michael W.Y. Chan5Hon-Yi Lin6Hon-Yi Lin7Wen-Yen Chiou8Wen-Yen Chiou9Ru-Inn Lin10Chien-An Chen11Moon-Sing Lee12Moon-Sing Lee13Chen-Lin Chi14Chen-Lin Chi15Liang-Cheng Chen16Liang-Cheng Chen17Li-Wen Huang18Li-Wen Huang19Chia-Hui Chew20Chia-Hui Chew21Feng-Chun Hsu22Hsuan-Ju Yang23Shih-Kai Hung24Shih-Kai Hung25Department of Medical Research, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanResearch Center for Environmental Medicine, Kaohsiung Medical University, Kaohsiung, TaiwanDepartment of Biomedical Sciences, National Chung Cheng University, Chia-Yi, TaiwanEpigenomics and Human Disease Research Center, National Chung Cheng University, Chia-Yi, TaiwanCenter for Innovative Research on Aging Society (CIRAS), National Chung Cheng University, Chia-Yi, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanDepartment of Radiation Oncology, Zhongxing Branch, Taipei City Hospital, Taipei, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanDepartment of Pathology, Chiayi Chang Gung Memorial Hospital, Chia-Yi, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanDepartment of Radiation Oncology, Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Chia-Yi, TaiwanSchool of Medicine, Tzu Chi University, Hualian, TaiwanPredicting and overcoming radioresistance are crucial in radiation oncology, including in managing oral squamous cell carcinoma (OSCC). First, we used RNA-sequence to compare expression profiles of parent OML1 and radioresistant OML1-R OSCC cells in order to select candidate genes responsible for radiation sensitivity. We identified IRAK2, a key immune mediator of the IL-1R/TLR signaling, as a potential target in investigating radiosensitivity. In four OSCC cell lines, we observed that intrinsically low IRAK2 expression demonstrated a radioresistant phenotype (i.e., OML1-R and SCC4), and vice versa (i.e., OML1 and SCC25). Next, we overexpressed IRAK2 in low IRAK2-expression OSCC cells and knocked it down in high IRAK2-expression cells to examine changes of irradiation response. After ionizing radiation (IR) exposure, IRAK2 overexpression enhanced the radiosensitivity of radioresistant cells and synergistically suppressed OSCC cell growth both in vitro and in vivo, and vice versa. We found that IRAK2 overexpression restored and enhanced radiosensitivity by enhancing IR-induced cell killing via caspase-8/3-dependent apoptosis. OSCC patients with high IRAK2 expression had better post-irradiation local control than those with low expression (i.e., 87.4% vs. 60.0% at five years, P = 0.055), showing that IRAK2 expression was associated with post-radiation recurrence. Multivariate analysis confirmed high IRAK2 expression as an independent predictor for local control (HR, 0.11; 95% CI, 0.016 – 0.760; P = 0.025). In conclusion, IRAK2 enhances radiosensitivity, via modulating caspase 8/3-medicated apoptosis, potentially playing double roles as a predictive biomarker and a novel therapeutic target in OSCC.https://www.frontiersin.org/articles/10.3389/fonc.2021.647175/fullIRAK2radioresistantapoptosisradiosensitizationoral squamous cell carcinoma |
| spellingShingle | Chih-Chia Yu Chih-Chia Yu Michael W.Y. Chan Michael W.Y. Chan Michael W.Y. Chan Michael W.Y. Chan Hon-Yi Lin Hon-Yi Lin Wen-Yen Chiou Wen-Yen Chiou Ru-Inn Lin Chien-An Chen Moon-Sing Lee Moon-Sing Lee Chen-Lin Chi Chen-Lin Chi Liang-Cheng Chen Liang-Cheng Chen Li-Wen Huang Li-Wen Huang Chia-Hui Chew Chia-Hui Chew Feng-Chun Hsu Hsuan-Ju Yang Shih-Kai Hung Shih-Kai Hung IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma Frontiers in Oncology IRAK2 radioresistant apoptosis radiosensitization oral squamous cell carcinoma |
| title | IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma |
| title_full | IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma |
| title_fullStr | IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma |
| title_full_unstemmed | IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma |
| title_short | IRAK2, an IL1R/TLR Immune Mediator, Enhances Radiosensitivity via Modulating Caspase 8/3-Mediated Apoptosis in Oral Squamous Cell Carcinoma |
| title_sort | irak2 an il1r tlr immune mediator enhances radiosensitivity via modulating caspase 8 3 mediated apoptosis in oral squamous cell carcinoma |
| topic | IRAK2 radioresistant apoptosis radiosensitization oral squamous cell carcinoma |
| url | https://www.frontiersin.org/articles/10.3389/fonc.2021.647175/full |
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