A longitudinal study of transcriptional profiling of carbon-ions exposure on the lung
Zhou Cheng1, Wen Lei2, Su Shengfa3, Lu Shun4, Xu Zhiyuan5, Cheng Hao6, Shan Changguo2, Lai Mingyao2, Cai Linbo2, Chen Longhua1, Chen Ming7, Zhou Zhaoming2
1Department of Radiation Oncology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; 2Department of Oncology, Guangdong Sanjiu Brain Hospital, Guangzhou 510510, China; 3Department of Oncology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China; 4Department of Radiation Oncology, Sichuan Cancer Hospital & Institute, University of Electronic Science and Technology of China, Chengdu 610041, China; 5Department of Radiation Oncology, the University of Hong Kong-Shenzhen Hospital, Shenzhen 518053, China; 6Department of Radiation Oncology, Chenzhou First People′s Hospital, Chenzhou 423002, China; 7Department of Radiation Oncology, Sun Yat-sen University Cancer Center, Guangzhou 510060, China
Abstract：Objective To investigate the expression changes at the transcriptional level in normal lung tissues of mice after exposure to heavy ion radiation for different durations at different doses, aiming to provide evidence for exploring sensitive genes of heavy ion radiation, heavy ion radiation effect and the damage mechanism. Methods Experiments on the temporal kinetics:the whole thorax of mice was irradiated with 14.5Gy carbon-ions and the total RNA of lung tissue was extracted at 3days, 7days, 3 weeks and 24 weeks. In dose-dependent experiment, the total RNA of lung tissue was extracted at 1 week after irradiated with a growing thoracic dose of 0, 7.5, 10.5, 12.5, 14.5, 17.5 and 20Gy. Protein-to-protein interaction (PPI) analysis and gene-ontology biological process enrichment analysis were performed on significant differentially expressed genes (DEGs). Results A clearly differential expression patterns were observed at 3-day (acute stage), 1-week (subacute stage), 3-week (inflammatory stage) and 24-week (fibrosis stage) following 14.5Gy carbon-ions irradiation. Among those, the 3-day time point was found to be the mostly different from the other time points, whereas the 7-day time point had the highest uniformity with the other time points. Cellular apoptosis was the main type of cell death in normal lung tissues following carbon-ions exposure. The interactive genes of Phlda3, GDF15, Mgmt and Bax were identified as the radiosensitive genes, and Phlda3 was the center (R=0.76, P<0.001). Conclusion The findings in this study provide transcriptional insights into the biological mechanism underlying normal lung tissue toxicity induced by carbon-ions.
Zhou Cheng,Wen Lei,Su Shengfa et al. A longitudinal study of transcriptional profiling of carbon-ions exposure on the lung[J]. Chinese Journal of Radiation Oncology, 2021, 30(7): 721-727.
[1] Chen GT, Castro JR, Quivey JM. Heavy charged particle radiotherapy[J]. Annu Rev Biophys Bioeng, 1981, 10:499-529. DOI:10.1146/annurev.bb.10.060181.002435. [2] Baumann M, Krause M, Overgaard J, et al. Radiation oncology in the era of precision medicine[J]. Nat Rev Cancer, 2016, 16(4):234-249. DOI:10.1038/nrc.2016.18. [3] Suit H, DeLaney T, Goldberg S, et al. Proton vs. carbon ion beams in the definitive radiation treatment of cancer patients[J]. Radiother Oncol, 2010, 95(1):3-22. DOI:10.1016/j.radonc.2010.01.015. [4] Kamada T, TsujⅡ H, Blakely EA, et al. Carbon ion radiotherapy in Japan:an assessment of 20 years of clinical experience[J]. Lancet Oncol, 2015, 16(2):e93-e100. DOI:10.1016/S1470-2045(14)70412-7. [5] Yamamoto N, Miyamoto T, Nakajima M, et al. A dose escalation clinical trial of single-fraction carbon ion radiotherapy for peripheral stage Ⅰ non-small cell lung cancer[J]. J Thorac Oncol, 2017, 12(4):673-680. DOI:10.1016/j.jtho.2016.12.012. [6] Karube M, Yamamoto N, Nakajima M, et al. Single-fraction carbon-ion radiation therapy for patients 80 years of age and older with stage Ⅰ non-small cell lung cancer[J]. Int J Radiat Oncol Biol Phys, 2016, 95(1):542-548. DOI:10.1016/j.ijrobp.2015.11.034. [7] Miyamoto T, Baba M, Sugane T, et al. Carbon ion radiotherapy for stage Ⅰ non-small cell lung cancer using a regimen of four fractions during 1 week[J]. J Thorac Oncol, 2007, 2(10):916-926. DOI:10.1097/JTO.0b013e3181560a68. [8] Zhou C, Jones B, Moustafa M, et al. Quantitative assessment of radiation dose and fractionation effects on normal tissue by utilizing a novel lung fibrosis index model[J]. Radiat Oncol, 2017, 12(1):172-179. DOI:10.1186/s13014-017-0912-y. [9] Zhou C, Jones B, Moustafa M, et al. Determining RBE for development of lung fibrosis induced by fractionated irradiation with carbon ions utilizing fibrosis index and high-LET BED model[J]. Clin Transl Radiat Oncol, 2019, 14(1):25-32. DOI:10.1016/j.ctro.2018.10.005. [10] Kamada T, TsujⅡ H, Blakely EA, et al. Carbon ion radiotherapy in Japan:an assessment of 20 years of clinical experience[J]. Lancet Oncol, 2015, 16(2):e93-e100. DOI:10.1016/S1470-2045(14)70412-7. [11] 周美娟,周兆明,文磊,等. 基于CT参数分析模型评估放射诱导小鼠肺纤维化剂量-效应关系研究[J]. 中华放射肿瘤学杂志,2019, 28(8):601-605. DOI:10.3760/cma.j.issn.1004-4221.2019.08.010 Zhou MJ, Zhou ZM, Wen L, et al. Dose-response relationship of radiation-induced pulmonary fibrosis in mouse models based on CT-derived parameters[J]. Chin J Radiat Oncol, 2019, 28(8):601-605. DOI:10.3760/cma.j.issn.1004-4221.2019.08.010 [12] 耿继武,刘浩,曹立基,等. 无创吸入式麻醉精准肺野照射装置在小鼠肺损伤研究中的应用[J]. 中国辐射卫生,2018, 27(2):109-113. DOI:10.13491/j.issn.1004-714x.2018.02.004. Geng JW,Li H, Cai LJ, et al. Application of non-invasive inhalation anesthesia precision thoracic irradiation device in a mouse model[J]. Chin J Radiol Heal, 2018, 27(2):109-113. DOI:10.13491/j.issn.1004-714x.2018.02.004. [13] Ritchie ME, Phipson B, Wu D, et al. limma powers differential expression analyses for RNA-sequencing and microarray studies[J]. Nucleic Acids Res, 2015, 43(7):e47. DOI:10.1093/nar/gkv007. [14] Szklarczyk D, Franceschini A, Wyder S, et al. STRING v10:protein-protein interaction networks, integrated over the tree of life[J]. Nucleic Acids Res, 2015, 43(D1): D447-D452. DOI:10.1093/nar/gku1003. [15] Ashburner M, Ball CA, Blake JA, et al. Gene ontology:tool for the unification of biology. The gene ontology consortium[J]. Nat Genet, 2000, 25(1):25-29. DOI:10.1038/75556. [16] Shannon P, Markiel A, Ozier O, et al. Cytoscape:a software environment for integrated models of biomolecular interaction networks[J]. Genome Res, 2003, 13(11):2498-2504. DOI:10.1101/gr.1239303. [17] Georgakilas AG, O′neill P, Stewart RD. Induction and repair of clustered DNA lesions:what do we know so far?[J]. Radiat Res, 2013, 180(1):100-109. DOI:10.1667/RR3041.1. [18] Zhou C, Moustafa MR, Cao L, et al. Modeling and multi-scale characterization of the quantitative imaging based fibrosis index reveals pathophysiological, transcriptome and proteomic correlates of lung fibrosis induced by fractionated irradiation[J]. Int J Cancer, 2019, 144(12):3160-3173. DOI:10.1002/ijc.32059. [19] Castro JR, Chen GT, Pitluck S, et al. Helium charged-particle radiotherapy of locally advanced carcinoma of the esophagus, stomach, and biliary tract[J]. Am J Clin Oncol, 1983, 6(6):629-637. [20] Castro JR. Heavy charged particle irradiation of human cancers[J]. Radiat Med, 1983, 1(1):70-75. [21] Char DH, Castro JR, Quivey JM, et al. Helium ion charged particle therapy for choroidal melanoma[J]. Ophthalmology, 1980, 87(6):565-570. DOI:10.1016/s0161-6420(80)35195-6.
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